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http://www.ncbi.nlm.nih.gov/pubmed/8670839 | 1. EMBO J. 1996 Jul 1;15(13):3377-84.
Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in
yeast.
Yamaguchi-Iwai Y(1), Stearman R, Dancis A, Klausner RD.
Author information:
(1)Cell Biology and Metabolism Branch, National Institute of Child Health and
Human Development, National Institutes of Health, Bethesda, MD, USA.
Iron deprivation of Saccharomyces cerevisiae induces transcription of genes
required for high-affinity iron uptake. AFT1 mediates this transcriptional
control. In this report, the 5'-flanking region of FET3, which encodes a
copper-dependent oxidase required for iron transport, was analyzed and found to
contain a DNA sequence responsible for AFT1-regulated gene expression. AFT1 was
capable of interacting specifically with this DNA sequence. A core element
within this DNA sequence necessary for the binding of AFT1 was also determined.
In vivo footprinting demonstrated occupancy of the AFT1 binding site in cells
deprived of iron and not in cells grown in the presence of iron. Thus, the
environmental signal resulting from iron deprivation was transduced through the
regulated binding of AFT1 to the FET3 promoter, followed by the activation of
transcription. A regulon of genes under the control of AFT1 could be defined.
AFT1 was able to bind to a consensus binding site (PyPuCACCCPu) in the 5' region
of FRE1, FRE2, FTR1, FTH1 and CCC2.
PMCID: PMC451901
PMID: 8670839 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12079930 | 1. Asian Cardiovasc Thorac Ann. 2002 Jun;10(2):107-10. doi:
10.1177/021849230201000203.
Coronary bypass surgery in patients on thyroxin replacement therapy.
Syed AU(1), El Watidy AF, Akhlaque NB, Wahba A, El Oakley RM, Imran K, Al
Bukhari EA, Al Fagih MR.
Author information:
(1)Prince Sultan Cardiac Center, Armed Forces Hospital, Riyadh, Saudi Arabia.
[email protected]
The outcome of coronary bypass surgery was analyzed in 25 patients who were on
thyroxin replacement therapy for chronic thyroid disorders at the time of
operation. It was hypothesized that if such patients were given only their
routine dose of thyroxin on the day of surgery, hemodynamic and
cardiorespiratory recovery may be poor. All the patients on thyroxin replacement
therapy were given their routine dose of thyroxin orally or via a nasogastric
tube in the perioperative period. No supplemental dose was used. Based on
preoperative levels of thyroid stimulating hormone, 68% of these patients were
biochemically hypothyroid prior to surgery. Analysis of a large number of
variables showed no difference in outcome against a control group who had no
previous thyroid problems. We conclude that routine thyroxin administration is
all that is required for a satisfactory outcome in patients undergoing coronary
bypass surgery while on thyroxin replacement therapy.
DOI: 10.1177/021849230201000203
PMID: 12079930 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17990503 | 1. Pac Symp Biocomput. 2007:328-39.
A cognitive evaluation of four online search engines for answering definitional
questions posed by physicians.
Yu H(1), Kaufman D.
Author information:
(1)University of Wisconsin-Milwaukee, Department of Health Sciences, 2400 E.
Hartford Avenue, PO Box 413, Milwaukee, WI 53210, USA.
The Internet is having a profound impact on physicians' medical decision making.
One recent survey of 277 physicians showed that 72% of physicians regularly used
the Internet to research medical information and 51% admitted that information
from web sites influenced their clinical decisions. This paper describes the
first cognitive evaluation of four state-of-the-art Internet search engines:
Google (i.e., Google and Scholar.Google), MedQA, Onelook, and PubMed for
answering definitional questions (i.e., questions with the format of "What is
X?") posed by physicians. Onelook is a portal for online definitions, and MedQA
is a question answering system that automatically generates short texts to
answer specific biomedical questions. Our evaluation criteria include quality of
answer, ease of use, time spent, and number of actions taken. Our results show
that MedQA outperforms Onelook and PubMed in most of the criteria, and that
MedQA surpasses Google in time spent and number of actions, two important
efficiency criteria. Our results show that Google is the best system for quality
of answer and ease of use. We conclude that Google is an effective search engine
for medical definitions, and that MedQA exceeds the other search engines in that
it provides users direct answers to their questions; while the users of the
other search engines have to visit several sites before finding all of the
pertinent information.
PMID: 17990503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23244628 | 1. Hum Genomics. 2012 Sep 1;6(1):17. doi: 10.1186/1479-7364-6-17.
Usability survey of biomedical question answering systems.
Bauer MA(1), Berleant D.
Author information:
(1)Department of Information Science, University of Arkansas at Little Rock,
Little Rock, AR 72204, USA. [email protected]
We live in an age of access to more information than ever before. This can be a
double-edged sword. Increased access to information allows for more informed and
empowered researchers, while information overload becomes an increasingly
serious risk. Thus, there is a need for intelligent information retrieval
systems that can summarize relevant and reliable textual sources to satisfy a
user's query. Question answering is a specialized type of information retrieval
with the aim of returning precise short answers to queries posed as natural
language questions. We present a review and comparison of three biomedical
question answering systems: askHERMES (http://www.askhermes.org/), EAGLi
(http://eagl.unige.ch/EAGLi/), and HONQA
(http://services.hon.ch/cgi-bin/QA10/qa.pl).
DOI: 10.1186/1479-7364-6-17
PMCID: PMC3500219
PMID: 23244628 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24394544 | 1. Exp Cell Res. 2014 Feb 15;321(2):201-8. doi: 10.1016/j.yexcr.2013.12.023. Epub
2014 Jan 3.
Lipid droplets fusion in adipocyte differentiated 3T3-L1 cells: a Monte Carlo
simulation.
Boschi F(1), Rizzatti V(2), Zamboni M(2), Sbarbati A(3).
Author information:
(1)Department of Neurological and Movement Sciences, University of Verona,
Strada Le Grazie 8, 37134 Verona, Italy; Department of Computer Science,
University of Verona, Strada Le Grazie 15, 37134 Verona, Italy. Electronic
address: [email protected].
(2)Department of Medicine, Geriatric Section, University of Verona, Piazzale
Stefani 1, 37126 Verona, Italy.
(3)Department of Neurological and Movement Sciences, University of Verona,
Strada Le Grazie 8, 37134 Verona, Italy.
Several human worldwide diseases like obesity, type 2 diabetes, hepatic
steatosis, atherosclerosis and other metabolic pathologies are related to the
excessive accumulation of lipids in cells. Lipids accumulate in spherical
cellular inclusions called lipid droplets (LDs) whose sizes range from fraction
to one hundred of micrometers in adipocytes. It has been suggested that LDs can
grow in size due to a fusion process by which a larger LD is obtained with
spherical shape and volume equal to the sum of the progenitors' ones. In this
study, the size distribution of two populations of LDs was analyzed in immature
and mature (5-days differentiated) 3T3-L1 adipocytes (first and second
populations, respectively) after Oil Red O staining. A Monte Carlo simulation of
interaction between LDs has been developed in order to quantify the size
distribution and the number of fusion events needed to obtain the distribution
of the second population size starting from the first one. Four models are
presented here based on different kinds of interaction: a surface weighted
interaction (R2 Model), a volume weighted interaction (R3 Model), a random
interaction (Random model) and an interaction related to the place where the LDs
are born (Nearest Model). The last two models mimic quite well the behavior
found in the experimental data. This work represents a first step in developing
numerical simulations of the LDs growth process. Due to the complex phenomena
involving LDs (absorption, growth through additional neutral lipid deposition in
existing droplets, de novo formation and catabolism) the study focuses on the
fusion process. The results suggest that, to obtain the observed size
distribution, a number of fusion events comparable with the number of LDs
themselves is needed. Moreover the MC approach results a powerful tool for
investigating the LDs growth process.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yexcr.2013.12.023
PMID: 24394544 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3197644 | 1. Endocrinology. 1988 Dec;123(6):2774-81. doi: 10.1210/endo-123-6-2774.
Iodothyronine 5'-deiodination in rat kidney microsomes: sensitivity to
propylthiouracil.
Goswami A(1), Rosenberg IN.
Author information:
(1)Department of Medicine, Framingham Union Hospital, Massachusetts 01701.
When activated by dithiothreitol, iodothyronine 5'-deiodinase (I-5'D) activity
in kidney microsomes is less sensitive to inhibition by propylthiouracil (PTU)
and iopanoate (IOP) at nanomolar, compared to micromolar, substrate
concentrations. The enzymatic activities at nanomolar substrate concentrations
are, however, completely eliminated in the presence of a combination of 10
microM IOP and 100 microM PTU. In this report we present evidence that 1) the
relative PTU insensitivity results from the residual activities of the high Km
enzyme which, while being very sensitive to PTU inhibition at micromolar
substrate concentrations, becomes progressively less PTU sensitive as substrate
concentrations decline relative to its Km; and 2) the relative IOP insensitivity
is due to the presence in kidney microsomes of a low Km enzyme which is
relatively insensitive to IOP, but highly sensitive to inhibition by PTU.
Classifying the deiodinases on the basis of PTU sensitivity, therefore, requires
that not only the thiol concentrations, but, as in the case of the type I
enzyme, also the substrate concentrations be specified. The PTU resistance of
the type I enzyme at nanomolar substrate concentrations suggests a role of this
enzyme in T3 neogenesis in PTU-treated animals.
DOI: 10.1210/endo-123-6-2774
PMID: 3197644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24073237 | 1. PLoS One. 2013 Sep 20;8(9):e75091. doi: 10.1371/journal.pone.0075091.
eCollection 2013.
Increased neurofilament light chain blood levels in neurodegenerative
neurological diseases.
Gaiottino J(1), Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, Bestwick
JP, Monsch AU, Regeniter A, Lindberg RL, Kappos L, Leppert D, Petzold A,
Giovannoni G, Kuhle J.
Author information:
(1)Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, London, United Kingdom ; Bone & Joint Research
Unit, John Vane Science Centre, Queen Mary University of London, London, United
Kingdom.
OBJECTIVE: Neuronal damage is the morphological substrate of persisting
neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of
neurons and their release into cerebrospinal fluid has shown encouraging results
as a biomarker for neurodegeneration. This study aimed to validate the
quantification of the Nf light chain (NfL) in blood samples, as a biofluid
source easily accessible for longitudinal studies.
METHODS: We developed and applied a highly sensitive electrochemiluminescence
(ECL) based immunoassay for quantification of NfL in blood and CSF.
RESULTS: Patients with Alzheimer's disease (AD) (30.8 pg/ml, n=20),
Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral
sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control
group of neurological patients without evidence of structural CNS damage
(control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002
for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar
differences were seen in corresponding CSF samples. CSF and serum levels
correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70,
p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of
serum NfL for separating ALS from healthy controls was 91.3% and 91.0%.
CONCLUSIONS: We developed and validated a novel ECL based sandwich immunoassay
for the NfL protein in serum (NfL(Umea47:3)); levels in ALS were more than
20-fold higher than in controls. Our data supports further longitudinal studies
of serum NfL in neurodegenerative diseases as a potential biomarker of on-going
disease progression, and as a potential surrogate to quantify effects of
neuroprotective drugs in clinical trials.
DOI: 10.1371/journal.pone.0075091
PMCID: PMC3779219
PMID: 24073237 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: J. Gaiottino reports no
disclosures; N. Norgren is employed by UmanDiagnostics AB, Sweden; R. Dobson, J.
Topping, A. Nissim, A. Malsapina, J.P. Bestwick, A.U. Monsch, A. Regeniter
report no disclosures; R.L. Lindberg has received research support from the
Swiss MS Society, Swiss National Science Foundation, European FP6 and IMI JU
programs, Roche Postdoc Fellowship Program (RPF-program), unrestricted research
grants from Novartis and Biogen. L. Kappos reports, the University Hospital
Basel as employer of Dr. Kappos has received and dedicated to research support
fees for board membership, consultancy or speaking, or grants, in the last 3
years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin,
CSL Behring, Eli Lilly, European Union, GeNeuro, Genmab, Gianni Rubatto
Foundation, Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis,
Novartis Research Foundation, Novonordisk, Peptimmune, Roche, Roche Research
Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research
Foundation, Teva, UCB, and Wyeth. D. Leppert is an employee of F. Hoffmann-La
Roche Ltd. A. Petzold reports no disclosure. G. Giovannoni has received research
grant support from Bayer–Schering Healthcare, Biogen–Idec, GW Pharma, Merck
Serono, Merz, Novartis, Teva and Sanofi–Aventis. He has received personal
compensation for participating on Advisory Boards in relation to clinical trial
design, trial steering committees and data and safety monitoring committees
from: Bayer–Schering Healthcare, Biogen–Idec, Eisai, Elan, Fiveprime, Genzyme,
Genentech, GSK, Ironwood, Merck–Serono, Novartis, Pfizer, Roche, Sanofi–Aventis,
Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. J. Kuhle has received
research support from the Swiss MS Society, Swiss ALS Society, Protagen AG,
Roche and Novartis and served in scientific advisory boards for
Genzyme/Sanofi-Aventis, Merck Serono and Novartis Pharma. His work is supported
by an ECTRIMS Research Fellowship Programme and by the “Forschungsfonds” of the
University of Basel, Switzerland. This does not alter the authors' adherence to
all the PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/24281236 | 1. Menopause. 2014 Jun;21(6):633-40. doi: 10.1097/GME.0000000000000134.
Efficacy and safety of flibanserin in postmenopausal women with hypoactive
sexual desire disorder: results of the SNOWDROP trial.
Simon JA(1), Kingsberg SA, Shumel B, Hanes V, Garcia M Jr, Sand M.
Author information:
(1)From the 1Women's Health and Research Consultants, George Washington
University School of Medicine, Washington, DC; 2University Hospitals Case
Medical Center, Cleveland, OH; 3Boehringer Ingelheim Pharmaceuticals Inc,
Ridgefield, CT; and 4Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim,
Germany.
OBJECTIVE: This study aimed to assess the efficacy and safety of flibanserin, a
serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in
postmenopausal women with hypoactive sexual desire disorder (HSDD).
METHODS: Naturally postmenopausal women with HSDD received flibanserin 100 mg
once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co-primary
endpoints were changes from baseline to week 24 in the number of satisfying
sexual events (SSEs) across 28 days and in the Female Sexual Function Index
(FSFI) desire domain score. Secondary endpoints included change from baseline in
Female Sexual Distress Scale-Revised (FSDS-R) Item 13 score (which assesses
distress due to low sexual desire), FSDS-R total score, and FSFI total score.
The Patient Benefit Evaluation was asked on treatment discontinuation.
RESULTS: There were significant improvements with flibanserin versus placebo in
the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI
desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (-0.8 [0.1]
vs -0.6 [0.1]), FSDS-R total score (-8.3 [0.6] vs -6.3 [0.6]), and FSFI total
score (4.2 [0.4] vs 2.7 [0.4]; all P < 0.01). More women on flibanserin (37.6%)
than women on placebo (28.0%) reported experiencing meaningful benefits from the
study medication on treatment discontinuation. The most frequent adverse events
associated with flibanserin were dizziness, somnolence, nausea, and headache.
CONCLUSIONS: In naturally postmenopausal women with HSDD, flibanserin, compared
with placebo, has been associated with improvement in sexual desire, improvement
in the number of SSEs, and reduced distress associated with low sexual desire,
and is well tolerated.
DOI: 10.1097/GME.0000000000000134
PMID: 24281236 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24242746 | 1. Ann Neurol. 2014 Jan;75(1):116-26. doi: 10.1002/ana.24052. Epub 2014 Jan 2.
Cerebrospinal fluid neurofilament concentration reflects disease severity in
frontotemporal degeneration.
Scherling CS(1), Hall T, Berisha F, Klepac K, Karydas A, Coppola G, Kramer JH,
Rabinovici G, Ahlijanian M, Miller BL, Seeley W, Grinberg LT, Rosen H, Meredith
J Jr, Boxer AL.
Author information:
(1)Memory and Aging Center, Department of Neurology, University of California,
San Francisco, San Francisco, CA.
OBJECTIVE: Cerebrospinal fluid (CSF) neurofilament light chain (NfL)
concentration is elevated in neurological disorders, including frontotemporal
degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL
levels in FTD.
METHODS: CSF NfL, amyloid-β1-42 (Aβ42), tau, and phosphorylated tau
concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene
carriers (NC2) of FTD-causing mutations, and 79 FTD (45 behavioral variant
frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16
semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer
disease, 6 Parkinson disease, and 17 corticobasal syndrome patients.
Correlations between CSF analyte levels were performed with neuropsychological
measures and the Clinical Dementia Rating scale sum of boxes (CDRsb).
Voxel-based morphometry of structural magnetic resonance images determined the
relationship between brain volume and CSF NfL.
RESULTS: Mean CSF NfL concentrations were higher in bvFTD, SD, and PNFA than
other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures,
correlated with CDRsb and neuropsychological measures in FTD, but not in other
diagnostic groups. Analyses in 2 independent FTD cohorts and a group of
autopsy-verified or biomarker-enriched cases confirmed the larger group
analysis. In FTD, gray and white matter volume negatively correlated with CSF
NfL concentration, such that individuals with the highest NfL levels exhibited
the most atrophy.
INTERPRETATION: CSF NfL is elevated in symptomatic FTD and correlates with
disease severity. This measurement may be a useful surrogate endpoint of disease
severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are
warranted.
© 2014 Child Neurology Society/American Neurological Association.
DOI: 10.1002/ana.24052
PMCID: PMC4020786
PMID: 24242746 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23763388 | 1. Acta Neurol Scand. 2013 Dec;128(6):e33-6. doi: 10.1111/ane.12151. Epub 2013
Jun 13.
Neurofilament light and heavy subunits compared as therapeutic biomarkers in
multiple sclerosis.
Kuhle J(1), Malmeström C, Axelsson M, Plattner K, Yaldizli O, Derfuss T,
Giovannoni G, Kappos L, Lycke J.
Author information:
(1)Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, London, UK; Department of Neurology, University
Hospital Basel, Basel, Switzerland.
BACKGROUND: Neurofilaments are promising biomarkers in multiple sclerosis (MS)
and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or
degeneration. In a previous study, neurofilament light chain (NfL) levels in CSF
of relapsing remitting (RR) patients with MS were normalized by natalizumab
treatment.
AIMS OF THE STUDY: We compared the coherence between NfL and neurofilament heavy
chain (NfH(SMI) (35) ) levels in longitudinal CSF samples in a subset of these
patients.
METHODS: In 30 patients with RRMS, CSF was obtained prior to and following
12 months of natalizumab treatment. NfH(SMI) (35) was measured by an
electrochemiluminescence-based immunoassay. NfL levels were determined
previously by the UmanDiagnostics NF-light(®) assay.
RESULTS: NfH(SMI) (35) decreased in 73.3% and NfL in 90% of the patients
following natalizumab treatment (32.4 vs 27.4 pg/ml, P = 0.002 and 820 vs
375 pg/ml, P < 0.0001). Patients experiencing a relapse showed higher NfH(SMI)
(35) levels compared with patients in remission (47.7 vs 27.6 pg/ml, n = 8,
P = 0.001). This difference was less obvious for NfL (1055 vs 725 pg/ml,
P = 0.256). In patients in remission, NfL levels were lower following
natalizumab treatment (830 vs 365 pg/ml, n = 20, P = 0.0002), whereas the same
comparison failed significance for NfH(SMI) (35) (28.3 vs 26.9 pg/ml,
P = 0.086).
CONCLUSIONS: We confirm previous findings, indicating reduced axonal damage
under natalizumab treatment by measuring NfH(SMI) (35) , using an assay with
independent methodology. In comparison with NfH(SMI) (35) , NfL changes were
more pronounced and the treatment effect also included patients in remission.
Our results suggest that NfL is superior over NfH(SMI) (35) as therapeutic
biomarker and is a promising candidate to measure neuroaxonal damage in MS
treatment trials.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/ane.12151
PMID: 23763388 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7477166 | 1. N Engl J Med. 1995 Dec 7;333(23):1522-7. doi: 10.1056/NEJM199512073332302.
Thyroid hormone treatment after coronary-artery bypass surgery.
Klemperer JD(1), Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW,
Krieger K.
Author information:
(1)Department of Cardiothoracic Surgery, New York Hospital-Cornell University
Medical College, New York 10021, USA.
Comment in
N Engl J Med. 1995 Dec 7;333(23):1562-3. doi: 10.1056/NEJM199512073332310.
BACKGROUND: Thyroid hormone has many effects on the cardiovascular system.
During and after cardiopulmonary bypass, serum triiodothyronine concentrations
decline transiently, which may contribute to postoperative hemodynamic
dysfunction. We investigated whether the perioperative administration of
triiodothyronine (liothyronine sodium) enhances cardiovascular performance in
high-risk patients undergoing coronary-artery bypass surgery.
METHODS: We administered triiodothyronine or placebo to 142 patients with
coronary artery disease and depressed left ventricular function. The hormone was
administered as an intravenous bolus of 0.8 microgram per kilogram of body
weight when the aortic cross-clamp was removed after the completion of bypass
surgery and then as an infusion of 0.113 microgram per kilogram per hour for six
hours. Clinical and hemodynamic responses were serially recorded, as was any
need for inotropic or vasodilator drugs.
RESULTS: The patients' preoperative serum triiodothyronine concentrations were
normal (mean [+/- SD] value, 81 +/- 22 ng per deciliter [1.2 +/- 0.3 nmol per
liter]), and they decreased by 40 percent (P < 0.001) 30 minutes after the onset
of cardiopulmonary bypass. The concentrations in patients given intravenous
triiodothyronine became supranormal and were significantly higher than those in
patients given placebo (P < 0.001). However, the concentrations were once again
similar in the two groups 24 hours after surgery. The mean postoperative cardiac
index was higher in the triiodothyronine group (2.97 +/- 0.72 vs. 2.67 +/- 0.61
liters per minute per square meter of body-surface area, P = 0.007), and
systemic vascular resistance was lower (1073 +/- 314 vs. 1235 +/- 387
dyn.sec.cm-5, P = 0.003). The two groups did not differ significantly in the
incidence of arrhythmia or the need for therapy with inotropic and vasodilator
drugs during the 24 hours after surgery, or in perioperative mortality and
morbidity.
CONCLUSIONS: Raising serum triiodothyronine concentrations in patients
undergoing coronary-artery bypass surgery increases cardiac output and lowers
systemic vascular resistance, but does not change outcome or alter the need for
standard postoperative therapy.
DOI: 10.1056/NEJM199512073332302
PMID: 7477166 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25192482 | 1. J Neurosurg. 2014 Nov;121(5):1232-8. doi: 10.3171/2014.7.JNS132474. Epub 2014
Sep 5.
Detection of neurofilament-H in serum as a diagnostic tool to predict injury
severity in patients who have suffered mild traumatic brain injury.
Gatson JW(1), Barillas J, Hynan LS, Diaz-Arrastia R, Wolf SE, Minei JP.
Author information:
(1)Departments of Surgery and.
OBJECT: In previous studies of traumatic brain injury (TBI), neural biomarkers
of injury correlate with injury severity and predict neurological outcome. The
object of this paper was to characterize neurofilament-H (NFL-H) as a predictor
of injury severity in patients who have suffered mild TBI (mTBI). Thus, the
authors hypothesized that phosphorylated NFL-H (pNFL-H) levels are higher in
mTBI patients than in healthy controls and identify which subjects experienced a
more severe injury such as skull fractures, intracranial hemorrhaging, and/or
contusions as detected by CT scans.
METHODS: In this prospective clinical study, blood (8 ml) was collected from
subjects (n = 34) suffering from mTBI (as defined by the American Congress of
Rehabilitation and Glasgow Coma Scale scores between 13 and 15) at Parkland
Hospital, Dallas, Texas, on Days 1 and 3 after injury). Additional clinical
findings from the CT scans were also used to categorize the TBI patients into
those with and those without clinical findings on the scans (CT+ and CTgroups,
respectively). The serum levels of pNFL-H were measured using the enzyme-linked
immunosorbent assay.
RESULTS: Compared with healthy controls, the mTBI patients exhibited a
significant increase in the serum levels of pNFL-H on Days 1 (p = 0.00001) and 3
(p = 0.0001) after TBI. An inverse correlation was observed between pNFL-H serum
levels and Glasgow Coma Scale scores, which was significant. Additionally, using
receiver operating characteristic curve analysis to compare the mTBI cases with
controls to determine sensitivity and specificity, an area under the curve of
100% was achieved for both (p = 0.0001 for both). pNFL-H serum levels were only
significantly higher on Day 1 in mTBI patients in the CT+ group (p < 0.008)
compared with the CT- group. The area under the curve (82.5%) for the CT+ group
versus the CT- group was significant (p = 0.021) with a sensitivity of 87.5% and
a specificity of 70%, using a cutoff of 1071 pg/ml of pNFL-H in serum.
CONCLUSIONS: This study describes the serum profile of pNFL-H in patients
suffering from mTBI with and without CT findings on Days 1 and 3 after injury.
These results suggest that detection of pNFL-H may be useful in determining
which individuals require CT imaging to assess the severity of their injury.
DOI: 10.3171/2014.7.JNS132474
PMID: 25192482 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12643405 | 1. Ann Thorac Surg. 2002 Dec;74(6):2121-5. doi: 10.1016/s0003-4975(02)04082-1.
Excess coronary artery bypass graft mortality among women with hypothyroidism.
Zindrou D(1), Taylor KM, Bagger JP.
Author information:
(1)Cardiothoracic Directorate, Hammersmith Hospital, London, England.
BACKGROUND: The impact of thyroid disease on patients undergoing coronary artery
bypass grafting has been reported in only small series of selected patients.
METHODS: We investigated 30-day mortality of patients on thyroxine replacement
therapy undergoing isolated coronary artery bypass grafting from 1993 to 2000
and identified variables of importance for outcome.
RESULTS: A total of 3,631 patients (606 women) had isolated coronary artery
bypass grafting of whom 58 patients (30 women) were treated for hypothyroidism.
The mortality rate was higher among women with thyroxine replacement (16.7%, 95%
confidence interval [CI] 5.6 to 34.7) than those without thyroxine replacement
(5.9%, 95% CI 4.1 to 8.2; p = 0.02) and no difference between men with (3.6%,
95% CI 0.1 to 17.8) and without (2.6%, 95% CI 2.0 to 3.2) thyroxine treatment (p
= 0.8). Intake of diuretics (p < 0.001) was directly associated with mortality
whereas intake of aspirin (p = 0.01), levothyroxine dose (p = 0.03), and serum
thyroxine level (p = 0.01) were inversely associated with mortality among women
on thyroxine replacement.
CONCLUSIONS: Women on thyroxine replacement therapy undergoing coronary artery
bypass grafting had an increased mortality rate. We speculate that insufficient
thyroid hormone replacement could partly play a role in this outcome.
DOI: 10.1016/s0003-4975(02)04082-1
PMID: 12643405 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22132139 | 1. PLoS One. 2011;6(11):e27770. doi: 10.1371/journal.pone.0027770. Epub 2011 Nov
23.
Global mapping of H3K4me1 and H3K4me3 reveals the chromatin state-based cell
type-specific gene regulation in human Treg cells.
Tian Y(1), Jia Z, Wang J, Huang Z, Tang J, Zheng Y, Tang Y, Wang Q, Tian Z, Yang
D, Zhang Y, Fu X, Song J, Liu S, van Velkinburgh JC, Wu Y, Ni B.
Author information:
(1)Institute of Immunology, PLA, Third Military Medical University, Chongqing,
People's Republic of China.
Regulatory T cells (Treg) contribute to the crucial immunological processes of
self-tolerance and immune homeostasis. Genomic mechanisms that regulate cell
fate decisions leading to Treg or conventional T cells (Tconv) lineages and
those underlying Treg function remain to be fully elucidated, especially at the
histone modification level. We generated high-resolution genome-wide
distribution maps of monomethylated histone H3 lysine 4 (H3K4me1) and
trimethylated H3K4 (H3K4me3) in human CD4(+)CD25(+)FOXP3(+) Tregs and
CD4(+)CD25(+)FOXP3(-) activated (a)Tconv cells by DNA sequencing-by-synthesis.
2115 H3K4me3 regions corresponded to proximal promoters; in Tregs, the genes
associated with these regions included the master regulator FOXP3 and the
chemokine (C-C motif) receptor 7 (CCR7). 41024 Treg-specific H3K4me1 regions
were identified. The majority of the H3K4me1 regions differing between Treg and
aTconv cells were located at promoter-distal sites, and in vitro reporter gene
assays were used to evaluate and identify novel enhancer activity. We provide
for the first time a comprehensive genome-wide dataset of lineage-specific
H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control cell
type-specific gene regulation. This basic principle is likely not restricted to
the two closely-related T cell populations, but may apply generally to somatic
cell lineages in adult organisms.
DOI: 10.1371/journal.pone.0027770
PMCID: PMC3223197
PMID: 22132139 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/15474419 | 1. DNA Repair (Amst). 2004 Dec 2;3(12):1579-90. doi:
10.1016/j.dnarep.2004.06.012.
Role of mismatch-specific uracil-DNA glycosylase in repair of
3,N4-ethenocytosine in vivo.
Jurado J(1), Maciejewska A, Krwawicz J, Laval J, Saparbaev MK.
Author information:
(1)Groupe Réparation de l'AND, CNRS UMR 8113, LBPA-ENS Cachan, Institut Gustave
Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
The 3,N(4)-ethenocytosine (epsilon C) residue might have biological role in vivo
since it is recognized and efficiently excised in vitro by the E. coli
mismatch-specific uracil-DNA glycosylase (MUG) and the human thymine-DNA
glycosylase (hTDG). In the present work we have generated mug defective mutant
of E. coli by insertion of a kanamycin cassette to assess the role of MUG in
vivo. We show that human TDG complements the enzymatic activity of MUG when
expressed in a mug mutant. The epsilon C-DNA glycosylase defective strain did
not exhibit spontaneous mutator phenotype and did not show unusual sensitivity
to any of the following DNA damaging treatments: methylmethanesulfonate,
N-methyl-N'-nitro-N-nitrosoguanidine, ultraviolet light, H(2)O(2), paraquat.
However, plasmid DNA damaged by 2-chloroacetaldehyde treatment in vitro was
inactivated at a greater rate in a mug mutant than in wild-type host, suggesting
that MUG is required for the in vivo processing of the ethenobases. In addition,
2-chloroacetaldehyde treatment induces preferentially G.C --> C.G and A.T -->
T.A transversions in mug mutant. Comparison of the mutation frequencies induced
by the site-specifically incorporated epsilon C residue in E. coli wild-type
versus mug indicates that MUG repairs more than 80% of epsilon C residues in
vivo. Furthermore, the results show that nucleotide excision repair and
recombination are not involved in the processing of epsilon C in E. coli. Based
on the mutagenesis data we suggest that epsilon C may be less toxic and less
mutagenic than expected. The increased spontaneous mutation rate for G.C --> A.T
transition in the ung mug double mutant as compared to the single ung mutant
suggest that MUG may be a back-up repair enzyme to the classic uracil-DNA
glycosylase.
DOI: 10.1016/j.dnarep.2004.06.012
PMID: 15474419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22675617 | 1. Anemia. 2012;2012:926787. doi: 10.1155/2012/926787. Epub 2012 May 22.
Towards a molecular understanding of the fanconi anemia core complex.
Hodson C(1), Walden H.
Author information:
(1)Protein Structure and Function Laboratory, Lincoln's Inn Fields Laboratories,
London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London
WC2A 3LY, UK.
Fanconi Anemia (FA) is a genetic disorder characterized by the inability of
patient cells to repair DNA damage caused by interstrand crosslinking agents.
There are currently 14 verified FA genes, where mutation of any single gene
prevents repair of DNA interstrand crosslinks (ICLs). The accumulation of ICL
damage results in genome instability and patients having a high predisposition
to cancers. The key event of the FA pathway is dependent on an eight-protein
core complex (CC), required for the monoubiquitination of each member of the
FANCD2-FANCI complex. Interestingly, the majority of patient mutations reside in
the CC. The molecular mechanisms underlying the requirement for such a large
complex to carry out a monoubiquitination event remain a mystery. This paper
documents the extensive efforts of researchers so far to understand the
molecular roles of the CC proteins with regard to its main function in the FA
pathway, the monoubiquitination of FANCD2 and FANCI.
DOI: 10.1155/2012/926787
PMCID: PMC3364535
PMID: 22675617 |
http://www.ncbi.nlm.nih.gov/pubmed/21234386 | 1. Sarcoma. 2011;2011:593708. doi: 10.1155/2011/593708. Epub 2010 Dec 22.
The role of chemokine receptor CXCR4 in the biologic behavior of human soft
tissue sarcoma.
Kim RH(1), Li BD, Chu QD.
Author information:
(1)Louisiana State University Health Sciences Center - Shreveport and
Feist-Weiller Cancer Center, Shreveport, LA 71130-3932, USA.
The molecular basis of sarcoma remains poorly understood. However, recent
studies have begun to uncover some of the molecular pathways involved in
sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma
development and has been found to be a prognostic marker for poor clinical
outcome. There is growing evidence that overexpression of CXCR4 plays a
significant role in development of metastatic disease, especially in directing
tumor cells towards the preferential sites of metastases in sarcoma, lung and
bone. Although further investigation is necessary to validate these pathways,
there is potential for clinical application, particularly in the use of
pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.
DOI: 10.1155/2011/593708
PMCID: PMC3017902
PMID: 21234386 |
http://www.ncbi.nlm.nih.gov/pubmed/17317766 | 1. Endocrinology. 2007 Jun;148(6):2870-7. doi: 10.1210/en.2007-0009. Epub 2007
Feb 22.
Adeno-associated virus-mediated expression of thyroid hormone receptor
isoforms-alpha1 and -beta1 improves contractile function in pressure
overload-induced cardiac hypertrophy.
Belke DD(1), Gloss B, Swanson EA, Dillmann WH.
Author information:
(1)Department of Medicine, 5063 Basic Sciences Building, University of
California-San Diego, La Jolla, CA 92093-0618, USA.
Pressure overload-induced cardiac hypertrophy leads to decreased contractile
performance, frequently progressing to heart failure. Cardiac hypertrophy and
heart failure can be accompanied by the so-called sick thyroid syndrome,
resulting in decreased serum T(3) levels along with decreased expression of
thyroid hormone receptors (TRalpha1 and TRbeta1) and sarco(endo)plasmic
reticulum Ca-ATPase (SERCA). Because the binding of T(3) occupied receptors to
the thyroid response elements in the SERCA promotor can increase gene
expression, we wanted to determine whether increasing TR expression in the
hypertrophied heart could also improve SERCA expression and cardiac function.
Mice subjected to aortic constriction to generate pressure overload-induced
hypertrophy were also subjected to gene therapy using adeno-associated virus
(AAV) expressing either TRalpha1 or TRbeta1, with LacZ expressing AAV serving as
control. After 8 wk of aortic constriction, a similar degree of hypertrophy was
observed in all three groups; however, mice treated with TRalpha1 or TRbeta1
showed improved contractile function. Administration of a physiological dose of
T(3) increased serum T(3) levels only into the lower range of normal. This T(3)
dose, with or without AAV TR treatment, did not result in any significant
increase in contractile performance. Calcium transients measured in isolated
myocytes also exhibited an enhanced rate of decay associated with TRalpha1 or
TRbeta1 treatment. Western blot analysis showed increased SERCA expression in
the TRalpha1- or TRbeta1-treated groups relative to the LacZ-treated control
group. These results demonstrate that increasing TR expression in the
hypertrophied heart is associated with an improvement in contractile function
and increased SERCA expression.
DOI: 10.1210/en.2007-0009
PMID: 17317766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18274647 | 1. EURASIP J Bioinform Syst Biol. 2007;2007(1):28576. doi: 10.1155/2007/28576.
Question processing and clustering in INDOC: a biomedical question answering
system.
Sondhi P(1), Raj P, Kumar VV, Mittal A.
Author information:
(1)Department of Electronics and Computer Engineering, Indian Institute of
Technology-Roorkee, Roorkee, India.
The exponential growth in the volume of publications in the biomedical domain
has made it impossible for an individual to keep pace with the advances. Even
though evidence-based medicine has gained wide acceptance, the physicians are
unable to access the relevant information in the required time, leaving most of
the questions unanswered. This accentuates the need for fast and accurate
biomedical question answering systems. In this paper we introduce INDOC--a
biomedical question answering system based on novel ideas of indexing and
extracting the answer to the questions posed. INDOC displays the results in
clusters to help the user arrive the most relevant set of documents quickly.
Evaluation was done against the standard OHSUMED test collection. Our system
achieves high accuracy and minimizes user effort.
DOI: 10.1155/2007/28576
PMCID: PMC3171333
PMID: 18274647 |
http://www.ncbi.nlm.nih.gov/pubmed/25934855 | 1. Neurology. 2015 Jun 2;84(22):2247-57. doi: 10.1212/WNL.0000000000001642. Epub
2015 May 1.
Neurofilament light chain: A prognostic biomarker in amyotrophic lateral
sclerosis.
Lu CH(1), Macdonald-Wallis C(1), Gray E(1), Pearce N(1), Petzold A(1), Norgren
N(1), Giovannoni G(1), Fratta P(1), Sidle K(1), Fish M(1), Orrell R(1), Howard
R(1), Talbot K(1), Greensmith L(1), Kuhle J(1), Turner MR(2), Malaspina A(2).
Author information:
(1)From the Centre for Neuroscience & Trauma (C.-H.L., G.G., J.K., A.M.),
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen
Mary University of London; Sobell Department of Motor Neuroscience and Movement
Disorders (C.-H.L., L.G.), Departments of Neuroinflammation (A.P.),
Neurodegenerative Disease (P.F.), Molecular Neuroscience (K.S.), and Clinical
Neuroscience (R.O.), and MRC Centre for Neuromuscular Diseases (R.O., L.G.), UCL
Institute of Neurology, London; MRC Integrative Epidemiology Unit (C.M.-W.),
University of Bristol; Nuffield Department of Clinical Neurosciences (E.G.,
K.T., M.R.T.), University of Oxford; Department of Medical Statistics (N.P.),
London School of Hygiene and Tropical Medicine, London, UK; UmanDiagnostics
(N.N.), Umeå, Sweden; Medicine Clinical Trial Unit (M.F.), Musgrove Park
Hospital, Taunton, UK; National Hospital for Neurology and Neurosurgery (R.O.,
R.H., A.M.), London, UK; Neurology (J.K.), University Hospital Basel,
Switzerland; North-East London and Essex MND Care and Research Centre (A.M.),
London; and Basildon and Thurrock University Hospitals NHS Foundation Trust
(A.M.), Basildon, UK.
(2)From the Centre for Neuroscience & Trauma (C.-H.L., G.G., J.K., A.M.),
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen
Mary University of London; Sobell Department of Motor Neuroscience and Movement
Disorders (C.-H.L., L.G.), Departments of Neuroinflammation (A.P.),
Neurodegenerative Disease (P.F.), Molecular Neuroscience (K.S.), and Clinical
Neuroscience (R.O.), and MRC Centre for Neuromuscular Diseases (R.O., L.G.), UCL
Institute of Neurology, London; MRC Integrative Epidemiology Unit (C.M.-W.),
University of Bristol; Nuffield Department of Clinical Neurosciences (E.G.,
K.T., M.R.T.), University of Oxford; Department of Medical Statistics (N.P.),
London School of Hygiene and Tropical Medicine, London, UK; UmanDiagnostics
(N.N.), Umeå, Sweden; Medicine Clinical Trial Unit (M.F.), Musgrove Park
Hospital, Taunton, UK; National Hospital for Neurology and Neurosurgery (R.O.,
R.H., A.M.), London, UK; Neurology (J.K.), University Hospital Basel,
Switzerland; North-East London and Essex MND Care and Research Centre (A.M.),
London; and Basildon and Thurrock University Hospitals NHS Foundation Trust
(A.M.), Basildon, UK. [email protected] [email protected].
Erratum in
Neurology. 2015 Sep 8;85(10):921. doi: 10.1212/WNL.0000000000001986.
OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in
relation to disease progression and survival in amyotrophic lateral sclerosis
(ALS).
METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured
in samples from 2 cohorts of patients with sporadic ALS and healthy controls,
recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control,
serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured
at regular intervals for up to 3 years. Change in ALS Functional Rating
Scale-Revised score was used to assess disease progression. Survival was
evaluated using Cox regression and Kaplan-Meier analysis.
RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy
controls with high sensitivity (97%, 89%, 90%, respectively) and specificity
(95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels
(r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in
patients with ALS compared with controls in both cohorts, and maintained a
relatively constant expression during follow-up. Blood NfL levels at recruitment
were strong, independent predictors of survival. The highest tertile of blood
NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval
1.98-7.94, p < 0.001).
CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with
prognostic value in ALS. The individually relatively stable levels
longitudinally offer potential for NfL as a pharmacodynamic biomarker in future
therapeutic trials.
CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL
electrochemiluminescence immunoassay accurately distinguishes patients with
sporadic ALS from healthy controls.
© 2015 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000001642
PMCID: PMC4456658
PMID: 25934855 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20852673 | 1. Clin Interv Aging. 2010 Sep 7;5:259-70. doi: 10.2147/cia.s6920.
Advantages of dietary, exercise-related, and therapeutic interventions to
prevent and treat sarcopenia in adult patients: an update.
Waters DL(1), Baumgartner RN, Garry PJ, Vellas B.
Author information:
(1)Department of Preventive and Social Medicine, Dunedin School of Medicine,
University of Otago, Dunedin, New Zealand.
Sarcopenia is the loss of skeletal muscle mass and function with aging. Although
the term sarcopenia was first coined in 1989, its etiology is still poorly
understood. Moreover, a consensus for defining sarcopenia continues to elude us.
Sarcopenic changes in the muscle include losses in muscle fiber quantity and
quality, alpha-motor neurons, protein synthesis rates, and anabolic and sex
hormone production. Other factors include basal metabolic rate, increased
protein dietary requirements, and chronic inflammation secondary to age-related
changes in cytokines and oxidative stress. These changes lead to decreased
overall physical functioning, increased frailty, falls risk, and ultimately the
loss of independent living. Because the intertwining relationships of these
factors are complex, effective treatment options are still under investigation.
The published data on sarcopenia are vast, and this review is not intended to be
exhaustive. The aim of this review is to provide an update on the current
knowledge of the definition, etiology, consequences, and current clinical trials
that may help address this pressing public health problem for our aging
populations.
DOI: 10.2147/cia.s6920
PMCID: PMC2938033
PMID: 20852673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15072569 | 1. J Endocrinol. 2004 Apr;181(1):85-90. doi: 10.1677/joe.0.1810085.
Renal and hepatic distribution of type I and type III iodothyronine deiodinase
protein in chicken.
Verhoelst CH(1), Van Der Geyten S, Darras VM.
Author information:
(1)Laboratory of Comparative Endocrinology, Zoological Institute, Naamsestraat
61, B-3000 Leuven, Belgium. [email protected]
Iodothyronine deiodinase in vitro activity studies in the chicken showed the
presence of type I and type III iodothyronine deiodinase activity in both liver
and kidney. Due to the lack of a specific antiserum the cellular localization of
the deiodinase proteins could not be revealed until now. In the present study,
specific antisera were used to study the renal and hepatic distribution of type
I and type III iodothyronine deiodinase protein in the chicken.
Immunocytochemical staining of liver tissue led to an immunopositive signal in
the hepatocytes in general. Moreover, a zonal distribution could be detected for
both enzymes. Maximum protein expression was shown in a thin layer of
hepatocytes bordering the blood veins. Although pericentral localization of type
I deiodinase protein has been previously reported in the rat, no data were given
concerning type III deiodinase protein. In the present study, we report the
co-localization of both enzymes in the chicken. Co-expression of the deiodinases
was also found in the kidney. Expression of both proteins was associated with
the tubular epithelial cells and with the transitional epithelium, and the inner
longitudinal and outer circular muscle layers of the ureter. No staining could
be detected in the lamina propria or in the fat tissue surrounding the ureter.
DOI: 10.1677/joe.0.1810085
PMID: 15072569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24273040 | 1. J Infect Dis. 2014 Apr 1;209(7):1032-8. doi: 10.1093/infdis/jit633. Epub 2013
Nov 22.
Incidence and prevalence of intrasubtype HIV-1 dual infection in at-risk men in
the United States.
Wagner GA(1), Pacold ME, Kosakovsky Pond SL, Caballero G, Chaillon A, Rudolph
AE, Morris SR, Little SJ, Richman DD, Smith DM.
Author information:
(1)University of California San Diego, La Jolla, California.
Erratum in
J Infect Dis. 2014 Oct 1;210(7):1166.
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) dual infection (DI) has
been associated with decreased CD4 T-cell counts and increased viral loads;
however, the frequency of intrasubtype DI is poorly understood. We used
ultradeep sequencing (UDS) to estimate the frequency of DI in a primary
infection cohort of predominantly men who have sex with men (MSM).
METHODS: HIV-1 genomes from longitudinal blood samples of recently infected,
therapy-naive participants were interrogated with UDS. DI was confirmed when
maximum sequence divergence was excessive and supported by phylogenetic
analysis. Coinfection was defined as DI at baseline; superinfection was
monoinfection at baseline and DI at a later time point.
RESULTS: Of 118 participants, 7 were coinfected and 10 acquired superinfection.
Superinfection incidence rate was 4.96 per 100 person-years (95% confidence
interval [CI], 2.67-9.22); 6 occurred in the first year and 4 in the second.
Overall cumulative prevalence of intrasubtype B DI was 14.4% (95% CI,
8.6%-22.1%). Primary HIV-1 incidence was 4.37 per 100 person-years (95% CI,
3.56-5.36).
CONCLUSIONS: Intrasubtype DI was frequent and comparable to primary infection
rates among MSM in San Diego; however, superinfection rates declined over time.
DI is likely an important component of the HIV epidemic dynamics, and
development of stronger immune responses to the initial infection may protect
from superinfection.
DOI: 10.1093/infdis/jit633
PMCID: PMC3952674
PMID: 24273040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11145561 | 1. Endocrinology. 2001 Jan;142(1):13-20. doi: 10.1210/endo.142.1.7907.
Type 2 iodothyronin deiodinase transgene expression in the mouse heart causes
cardiac-specific thyrotoxicosis.
Pachucki J(1), Hopkins J, Peeters R, Tu H, Carvalho SD, Kaulbach H, Abel ED,
Wondisford FE, Ingwall JS, Larsen PR.
Author information:
(1)Thyroid Division, Brigham and Women's Hospital, Harvard Institute of
Medicine, Boston, Massachusetts 02115, USA.
Comment in
Endocrinology. 2001 Jan;142(1):11-2. doi: 10.1210/endo.142.1.7986.
Type 2 iodothyronine deiodinase (D(2)) catalyzes intracellular 3, 5, 3'
triiodothyronine (T(3)) production from thyroxine (T(4)), and its messenger RNA
mRNA is highly expressed in human, but not rodent, myocardium. The goal of this
study was to identify the effects of D(2) expression in the mouse myocardium on
cardiac function and gene expression. We prepared transgenic (TG) mice in which
human D(2) expression was driven by the alpha-MHC promoter. Despite high
myocardial D(2) activity, myocardial T(3) was, at most, minimally increased in
TG myocardium. Although, plasma T(3) and T(4), growth rate as well as the heart
weight was not affected by TG expression, there was a significant increase in
heart rate of the isolated perfused hearts, from 284 +/-12 to 350 +/- 7
beats/min. This was accompanied by an increase in pacemaker channel (HCN2) but
not alpha-MHC or SERCA II messenger RNA levels. Biochemical studies and
(31)P-NMR spectroscopy showed significantly lower levels of phosphocreatine and
creatine in TG hearts. These results suggest that even mild chronic myocardial
thyrotoxicosis, such as may occur in human hyperthyroidism, can cause
tachycardia and associated changes in high energy phosphate compounds
independent of an increase in SERCA II and alpha-MHC.
DOI: 10.1210/endo.142.1.7907
PMID: 11145561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17312023 | 1. J Cell Biol. 2007 Feb 26;176(5):565-71. doi: 10.1083/jcb.200610062. Epub 2007
Feb 20.
DNMT1 but not its interaction with the replication machinery is required for
maintenance of DNA methylation in human cells.
Spada F(1), Haemmer A, Kuch D, Rothbauer U, Schermelleh L, Kremmer E, Carell T,
Längst G, Leonhardt H.
Author information:
(1)Department of Biology II and 2Department of Chemistry, Ludwig Maximilians
University Munich, 82152 Planegg-Martinsried, Germany.
DNA methylation plays a central role in the epigenetic regulation of gene
expression in vertebrates. Genetic and biochemical data indicated that DNA
methyltransferase 1 (Dnmt1) is indispensable for the maintenance of DNA
methylation patterns in mice, but targeting of the DNMT1 locus in human HCT116
tumor cells had only minor effects on genomic methylation and cell viability. In
this study, we identified an alternative splicing in these cells that bypasses
the disrupting selective marker and results in a catalytically active DNMT1
protein lacking the proliferating cell nuclear antigen-binding domain required
for association with the replication machinery. Using a mechanism-based trapping
assay, we show that this truncated DNMT1 protein displays only twofold reduced
postreplicative DNA methylation maintenance activity in vivo. RNA
interference-mediated knockdown of this truncated DNMT1 results in global
genomic hypomethylation and cell death. These results indicate that DNMT1 is
essential in mouse and human cells, but direct coupling of the replication of
genetic and epigenetic information is not strictly required.
DOI: 10.1083/jcb.200610062
PMCID: PMC2064015
PMID: 17312023 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18274800 | 1. Basic Res Cardiol. 2008 Jul;103(4):308-18. doi: 10.1007/s00395-008-0697-0.
Epub 2008 Feb 15.
Long-term thyroid hormone administration reshapes left ventricular chamber and
improves cardiac function after myocardial infarction in rats.
Pantos C(1), Mourouzis I, Markakis K, Tsagoulis N, Panagiotou M, Cokkinos DV.
Author information:
(1)Dept. of Pharmacology, University of Athens, 75 Mikras Asias Ave., Goudi,
11527, Athens, Greece. [email protected]
Thyroid hormone (TH) is critical for tissue differentiation at early stages of
development, induces physiological hypertrophy and regulates the expression of
important contractile proteins such as myosin heavy chain (MHC) isoform and
calcium cycling proteins. Furthermore, TH seems to control the response to
stress by regulating important cardioprotective molecules such as heat shock
proteins (HSPs). Thus, the present study investigated whether TH administration
immediately after acute myocardial infarction can favourably remodel the
post-infarcted myocardium. Acute myocardial infarction was induced in rats by
coronary artery ligation (AMI, n=10), while SHAM-operated animals served as
controls (SHAM, n = 8). TH was administered for 13 weeks (AMI-THYR, n = 9).
Cardiac contractile function and left ventricular (LV) chamber remodelling was
assessed by serial echocardiography and in Langendorff heart preparations. AMI
significantly reduced LV ejection fraction (EF%); 30.0 (s.e.m, 2.3) Vs. 73.8
(1.8) in SHAM, P < 0.05. In addition, +dp/dt and -dp/dt (in mmHg/s) were 4,051
(343) and 2,333 (118) respectively for SHAM Vs. 2,102 (290) and 1,368 (181) for
AMI, P < 0.05. With TH treatment, EF% was increased to 49.5 (2.7) in AMI-THYR, P
< 0.05, while +dp/dt and -dp/dt (in mmHg/s) were 3,708 (231) and 2,035 (95) for
AMI-THYR, P < 0.05 Vs. AMI. A marked elevation of the expression of beta-MHC and
a reduced ratio of SERCA/Phospholamban were found in viable myocardium of AMI
hearts, which was prevented by TH. Furthermore, heat shock protein 70 myocardial
content was decreased in AMI hearts and was significantly increased after TH
treatment. An ellipsoidal reshaping of LV chamber was observed with TH; cardiac
sphericity index, (ratio of long/short axis, SI), was 1.98 (0.03) for SHAM, 1.52
(0.05) for AMI and 1.72(0.02) for AMI-THYR, P < 0.05. In conclusion, long-term
TH administration immediately after AMI results in sustained improvement of
cardiac haemodynamics.
DOI: 10.1007/s00395-008-0697-0
PMID: 18274800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22323818 | 1. Science. 2012 Feb 10;335(6069):709-12. doi: 10.1126/science.1214453.
Structure-based mechanistic insights into DNMT1-mediated maintenance DNA
methylation.
Song J(1), Teplova M, Ishibe-Murakami S, Patel DJ.
Author information:
(1)Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York,
NY 10065, USA.
DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate
gene expression, genome imprinting, and X-chromosome inactivation. We report on
the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex
containing a central hemimethylated CpG site. The methyl group of methylcytosine
is positioned within a shallow hydrophobic concave surface, whereas the cytosine
on the target strand is looped out and covalently anchored within the catalytic
pocket. The DNA is distorted at the hemimethylated CpG step, with side chains
from catalytic and recognition loops inserting through both grooves to fill an
intercalation-type cavity associated with a dual base flip-out on partner
strands. Structural and biochemical data establish how a combination of active
and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated
maintenance DNA methylation.
DOI: 10.1126/science.1214453
PMCID: PMC4693633
PMID: 22323818 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22278882 | 1. Nucleic Acids Res. 2012 May;40(10):4334-46. doi: 10.1093/nar/gks031. Epub 2012
Jan 25.
DNMT1 modulates gene expression without its catalytic activity partially through
its interactions with histone-modifying enzymes.
Clements EG(1), Mohammad HP, Leadem BR, Easwaran H, Cai Y, Van Neste L, Baylin
SB.
Author information:
(1)Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD
21231, USA.
While DNA methyltransferase1 (DNMT1) is classically known for its functions as a
maintenance methyltransferase enzyme, additional roles for DNMT1 in gene
expression are not as clearly understood. Several groups have shown that
deletion of the catalytic domain from DNMT1 does not abolish repressive activity
of the protein against a reporter gene. In our studies, we examine the repressor
function of catalytically inactive DNMT1 at endogenous genes. First, potential
DNMT1 target genes were identified by searching for genes up-regulated in HCT116
colon cancer cells genetically disrupted for DNMT1 (DNMT1(-/-) hypomorph cells).
Next, the requirement for DNMT1 activity for repression of these genes was
assessed by stably restoring expression of wild-type or catalytically inactive
DNMT1. Both wild-type and mutant proteins are able to occupy the promoters and
repress the expression of a set of target genes, and induce, at these promoters,
both the depletion of active histone marks and the recruitment of a H3K4
demethylase, KDM1A/LSD1. Together, our findings show that there are genes for
which DNMT1 acts as a transcriptional repressor independent from its
methyltransferase function and that this repressive function may invoke a role
for a scaffolding function of the protein at target genes.
DOI: 10.1093/nar/gks031
PMCID: PMC3378872
PMID: 22278882 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21669844 | 1. Integr Comp Biol. 2009 Jul;49(1):32-9. doi: 10.1093/icb/icp007. Epub 2009 Apr
17.
From ultra-soft slime to hard {alpha}-keratins: The many lives of intermediate
filaments.
Fudge DS(1), Winegard T, Ewoldt RH, Beriault D, Szewciw L, McKinley GH.
Author information:
(1)*Department of Integrative Biology, University of Guelph, Guelph, ON N1G-2W1,
Canada; Hatsopoulos Microfluids Laboratory, Department of Mechanical
Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Intermediate filaments are filaments 10 nm in diameter that make up an important
component of the cytoskeleton in most metazoan taxa. They are most familiar for
their role as the fibrous component of α-keratins such as skin, hair, nail, and
horn but are also abundant within living cells. Although they are almost
exclusively intracellular in their distribution, in the case of the defensive
slime produced by hagfishes, they are secreted. This article surveys the
impressive diversity of biomaterials that animals construct from intermediate
filaments and will focus on the mechanisms by which the mechanical properties of
these materials are achieved. Hagfish slime is a dilute network of hydrated
mucus and compliant intermediate filament bundles with ultrasoft material
properties. Within the cytoplasm of living cells, networks of intermediate
filaments form soft gels whose elasticity arises via entropic mechanisms. Single
intermediate filaments or bundles are also elastic, but substantially stiffer,
exhibiting modulus values similar to that of rubber. Hard α-keratins like wool
are stiffer still, an effect that is likely achieved via dehydration of the
intermediate filaments in these epidermal appendages. The diverse mechanisms
described here have been employed by animals to generate materials with
stiffness values that span an impressive eleven orders of magnitude.
DOI: 10.1093/icb/icp007
PMID: 21669844 |
http://www.ncbi.nlm.nih.gov/pubmed/16500889 | 1. Nucleic Acids Res. 2006 Feb 25;34(4):1182-8. doi: 10.1093/nar/gkl002. Print
2006.
Accuracy of DNA methylation pattern preservation by the Dnmt1 methyltransferase.
Goyal R(1), Reinhardt R, Jeltsch A.
Author information:
(1)Institut für Biochemie FB 08, Heinrich-Buff-Ring 58,
Justus-Liebig-Universität Giessen, 35392 Giessen, Germany.
DNA methyltransferase 1 (Dnmt1) has a central role in copying the pattern of DNA
methylation after replication which is one manifestation of epigenetic
inheritance. With oligonculeotide substrates we show that mouse Dnmt1 has a 30-
to 40-fold preference for hemimethylated DNA that is almost lost after addition
of fully methylated oligonucleotides. Using long hemimethylated DNA substrates
that carry defined methylation patterns and bisulfite analysis of the
methylation reaction products, we show a 15-fold preference for hemimethylated
CG sites. Dnmt1 moves along the DNA in a random walk methylating hemimethylated
substrates with high processivity (>50 sites are visited on average which
corresponds to linear diffusion over 6000 bp). The frequency of skipping sites
is very low (<0.3%) and there is no detectable flanking sequence preference.
CGCTC sites tend to terminate the processive methylation of DNA by Dnmt1.
Unmethylated DNA is modified non-processively with a preference for methylation
at CCGG sites. We simulate the propagation of methylation patterns using a
stochastic model with the specificity of Dnmt1 observed here and conclude that
either methylation of several sites is required to propagate the methylation
information over several cellular generations or additional epigenetic
information must be used.
DOI: 10.1093/nar/gkl002
PMCID: PMC1383621
PMID: 16500889 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21559294 | 1. PLoS One. 2011 May 3;6(5):e19524. doi: 10.1371/journal.pone.0019524.
Expression patterns and miRNA regulation of DNA methyltransferases in chicken
primordial germ cells.
Rengaraj D(1), Lee BR, Lee SI, Seo HW, Han JY.
Author information:
(1)WCU Biomodulation Major, Department of Agricultural Biotechnology and
Research Institute for Agriculture and Life Sciences, Seoul National University,
Seoul, Korea.
DNA methylation is widespread in most species, from bacteria to mammals, and is
crucial for genomic imprinting, gene expression, and embryogenesis. DNA
methylation occurs via two major classes of enzymatic reactions:
maintenance-type methylation catalyzed by DNA (cytosine-5-)-methyltransferase
(DNMT) 1, and de novo methylation catalyzed by DNMT 3 alpha (DNMT3A) and -beta
(DNMT3B). The expression pattern and regulation of DNMT genes in primordial germ
cells (PGCs) and germ line cells has not been sufficiently established in birds.
Therefore, we employed bioinformatics, RT-PCR, real-time PCR, and in situ
hybridization analyses to examine the structural conservation and conserved
expression patterns of chicken DNMT family genes. We further examined the
regulation of a candidate de novo DNA methyltransferase gene, cDNMT3B by
cotransfection of cDNMT3B 3'UTR- and cDNMT3B 3'UTR-specific miRNAs through a
dual fluorescence reporter assay. All cDNMT family members were differentially
detected during early embryonic development. Of interest, cDNMT3B expression was
highly detected in early embryos and in PGCs. During germ line development and
sexual maturation, cDNMT3B expression was reestablished in a female germ
cell-specific manner. In the dual fluorescence reporter assay, cDNMT3B
expression was significantly downregulated by four miRNAs: gga-miR-15c (25.82%),
gga-miR-29b (30.01%), gga-miR-383 (30.0%), and gga-miR-222 (31.28%). Our data
highlight the structural conservation and conserved expression patterns of
chicken DNMTs. The miRNAs investigated in this study may induce downregulation
of gene expression in chicken PGCs and germ cells.
DOI: 10.1371/journal.pone.0019524
PMCID: PMC3086922
PMID: 21559294 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22761581 | 1. PLoS Genet. 2012 Jun;8(6):e1002750. doi: 10.1371/journal.pgen.1002750. Epub
2012 Jun 28.
In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases.
Arand J(1), Spieler D, Karius T, Branco MR, Meilinger D, Meissner A, Jenuwein T,
Xu G, Leonhardt H, Wolf V, Walter J.
Author information:
(1)Department of Biological Sciences, Institute of Genetics/Epigenetics,
University of Saarland, Saarbrücken, Germany.
Comment in
Nat Rev Genet. 2012 Jul 18;13(8):520. doi: 10.1038/nrg3284.
The enzymatic control of the setting and maintenance of symmetric and
non-symmetric DNA methylation patterns in a particular genome context is not
well understood. Here, we describe a comprehensive analysis of DNA methylation
patterns generated by high resolution sequencing of hairpin-bisulfite amplicons
of selected single copy genes and repetitive elements (LINE1, B1,
IAP-LTR-retrotransposons, and major satellites). The analysis unambiguously
identifies a substantial amount of regional incomplete methylation maintenance,
i.e. hemimethylated CpG positions, with variant degrees among cell types.
Moreover, non-CpG cytosine methylation is confined to ESCs and exclusively
catalysed by Dnmt3a and Dnmt3b. This sequence position-, cell type-, and
region-dependent non-CpG methylation is strongly linked to neighboring CpG
methylation and requires the presence of Dnmt3L. The generation of a
comprehensive data set of 146,000 CpG dyads was used to apply and develop
parameter estimated hidden Markov models (HMM) to calculate the relative
contribution of DNA methyltransferases (Dnmts) for de novo and maintenance DNA
methylation. The comparative modelling included wild-type ESCs and mutant ESCs
deficient for Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3a/3b, respectively. The HMM
analysis identifies a considerable de novo methylation activity for Dnmt1 at
certain repetitive elements and single copy sequences. Dnmt3a and Dnmt3b
contribute de novo function. However, both enzymes are also essential to
maintain symmetrical CpG methylation at distinct repetitive and single copy
sequences in ESCs.
DOI: 10.1371/journal.pgen.1002750
PMCID: PMC3386304
PMID: 22761581 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21625467 | 1. PLoS One. 2011;6(5):e20154. doi: 10.1371/journal.pone.0020154. Epub 2011 May
20.
Unfaithful maintenance of methylation imprints due to loss of maternal nuclear
Dnmt1 during somatic cell nuclear transfer.
Wei Y(1), Huan Y, Shi Y, Liu Z, Bou G, Luo Y, Zhang L, Yang C, Kong Q, Tian J,
Xia P, Sun QY, Liu Z.
Author information:
(1)College of Life Science, Northeast Agricultural University of China, Harbin,
China.
The low success rate of somatic cell nuclear transfer (SCNT) in mammalian
cloning is largely due to imprinting problems. However, little is known about
the mechanisms of reprogramming imprinted genes during SCNT. Parental
origin-specific DNA methylation regulates the monoallelic expression of
imprinted genes. In natural fertilization, methylation imprints are established
in the parental germline and maintained throughout embryonic development.
However, it is unclear whether methylation imprints are protected from global
changes of DNA methylation in cloned preimplantation embryos. Here, we
demonstrate that cloned porcine preimplantation embryos exhibit demethylation at
differentially methylated regions (DMRs) of imprinted genes; in particular,
demethylation occurs during the first two cell cycles. By RNAi-mediated
knockdown, we found that Dnmt1 is required for the maintenance of methylation
imprints in porcine preimplantation embryos. However, no clear signals were
detected in the nuclei of oocytes and preimplantation embryos by
immunofluorescence. Thus, Dnmt1 is present at very low levels in the nuclei of
porcine oocytes and preimplantation embryos and maintains methylation imprints.
We further showed that methylation imprints were rescued in nonenucleated
metaphase II (MII) oocytes. Our results indicate that loss of Dnmt1 in the
maternal nucleus during SCNT significantly contributes to the unfaithful
maintenance of methylation imprints in cloned embryos.
DOI: 10.1371/journal.pone.0020154
PMCID: PMC3098883
PMID: 21625467 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/17560116 | 1. Eur J Cardiothorac Surg. 2007 Aug;32(2):333-9. doi:
10.1016/j.ejcts.2007.05.004. Epub 2007 Jun 7.
Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early
after acute myocardial infarction in rats.
Pantos C(1), Mourouzis I, Markakis K, Dimopoulos A, Xinaris C, Kokkinos AD,
Panagiotou M, Cokkinos DV.
Author information:
(1)Department of Pharmacology, University of Athens, 75 Mikras Asias Avenue,
11527 Goudi, Athens, Greece. [email protected]
OBJECTIVE: Cardiac remodeling of viable myocardium occurs after acute myocardial
infarction (AMI) and further contributes to cardiac dysfunction. The present
study explored whether thyroid hormone (TH) administered shortly after AMI in
rats can attenuate cardiac remodeling and improve cardiac function. TH regulates
important structural and regulatory proteins in the myocardium including myosin
isoform expression and calcium cycling proteins.
METHODS: AMI was induced in Wistar male rats by ligating left coronary artery
(AMI, n=10), while sham-operated rats were used as controls (SHAM, n=10).
Animals with acute myocardial infarction were also treated with 0.05% thyroid
powder in food (AMI-THYR, n=10). Within 2 weeks, cardiac function was impaired
as assessed by echocardiography and under isometric conditions in Langendorff
preparations.
RESULTS: Ejection fraction (EF%) was 71.5 (SEM, 2.7) in SHAM versus 30.0 (2.0)
in AMI, P<0.05. +dp/dt was 3886 (566) in SHAM versus 2266 (206) in AMI hearts,
P<0.05 and -dp/dt was 1860 (46) in SHAM versus 1633 (120) in AMI hearts, P=ns.
Such changes were associated with alterations in myosin isoform expression in
the non-infarcted area; AMI hearts expressed 34% alpha-MHC and 66% beta-MHC
versus 52% alpha-MHC and 48% beta-MHC in SHAM, P<0.05, while the expression of
SERCA and phospholamban (PLB) remained unchanged. Furthermore, a mismatch of
left ventricular size and cardiac mass (2*Posterior Wall thickness/LVIDd was
decreased) was observed. After TH treatment, AMI-THYR hearts expressed 71%
alpha-MHC and 29% beta-MHC, P<0.05 versus SHAM and AMI and the ratio of
SERCA/PLB was increased by 2.0-fold, P<0.05 versus SHAM and AMI. These changes
corresponded to a marked improvement in cardiac function; EF% was raised to 45.8
(1.7), P<0.05 versus AMI while +dp/dt and -dp/dt were 3800 (435) and 2600 (200),
respectively, in AMI-THYR hearts, P<0.05 versus AMI. The ratio of 2*Posterior
Wall thickness/LVIDd was normalized.
CONCLUSIONS: Thyroid hormone administration early after infarction attenuates
cardiac remodeling and significantly improves myocardial performance.
DOI: 10.1016/j.ejcts.2007.05.004
PMID: 17560116 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9536925 | 1. Clin Sci (Lond). 1998 Feb;94(2):165-73. doi: 10.1042/cs0940165.
Angiotensin-converting enzyme inhibition does not correct early defects in renal
and vascular permeability in diabetes mellitus.
Zietse R(1), Derkx FH, Weimar W, Schalekamp MA.
Author information:
(1)Department of Internal Medicine I, University Hospital Rotterdam-Dijkzigt,
The Netherlands.
1. In diabetes mellitus a selective increase in the excretion of albumin
generally precedes the occurrence of demonstrable loss of glomerular
size-selectivity. However, even in this (microalbuminuric) phase of diabetic
nephropathy a defect in glomerular barrier function can be demonstrated during
infusion of atrial natriuretic peptide. 2. The aim of this study was to
investigate whether angiotensin-converting enzyme inhibition could prevent the
proteinuric response to atrial natriuretic peptide in these patients. We
performed infusions of atrial natriuretic peptide (0.01 microgram min-1 kg-1) in
10 patients with insulin-dependent diabetes mellitus and microalbuminuria
(urinary albumin excretion 90 +/- 44 mg/day), both before and after 1 month of
treatment with enalapril (20 mg once daily). 3. Despite a 40% reduction in
proteinuria, angiotensin-converting enzyme inhibition did not prevent the atrial
natriuretic peptide-induced increase in protein excretion. Both before and
during angiotensin-converting enzyme inhibition, atrial natriuretic peptide
infusion resulted in a significant increase in the fractional excretion of large
dextran molecules, which is compatible with an increase in flow through large
unrestrictive 'shunt' pores. Atrial natriuretic peptide infusion also induced an
increase in the transcapillary escape rate of albumin and angiotensin-converting
enzyme inhibition also failed to prevent this effect of atrial natriuretic
peptide on peripheral capillary permeability. 4. We conclude that
angiotensin-converting enzyme inhibition during 1 month does not correct the
capillary barrier function defect in patients with diabetes mellitus and
microalbuminuria that is unmasked by atrial natriuretic peptide infusion.
DOI: 10.1042/cs0940165
PMID: 9536925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15019550 | 1. Atherosclerosis. 2004 Feb;172(2):383-9. doi:
10.1016/j.atherosclerosis.2003.11.013.
Abnormal capillary permeability and endothelial dysfunction in hypertension with
comorbid Metabolic Syndrome.
Dell'Omo G(1), Penno G, Pucci L, Mariani M, Del Prato S, Pedrinelli R.
Author information:
(1)Dipartimento Cardiotoracico, Università di Pisa, 56100 Pisa, Italy.
PURPOSE: Metabolic Syndrome as defined by ATP III criteria, a constellation of
risk factors associated with insulin resistance, predisposes to premature
atherosclerosis and early coronary events. Whether that negative risk profile is
associated with endothelial dysfunction remains to be established.
MATERIALS AND METHODS: Transcapillary escape rate of albumin (TERalb), a measure
of capillary permeability and integrity of systemic capillary endothelium, and
forearm vasodilation to intra-arterial acetylcholine (ACH), an index of nitric
oxide (NO)-mediated vasomotor dysfunction, were assessed in 24 non-diabetic,
uncomplicated hypertensive men with Metabolic Syndrome according to ATP III
criteria (hypertension with at least two additional traits such as high
triglycerides, low HDL, abdominal obesity, impaired fasting or post-load plasma
glucose). Twelve age-matched lean normal hypertensive patients with normal lipid
and glucose profile and nine normotensive subjects were the controls. All
patients underwent lipids determination and fasting and post-OGTT insulin
assessment; HOMA-IR was the index of insulin resistance.
RESULTS: TERalb was higher in hypertensive patients with Metabolic Syndrome,
without differences between hypertensive and normotensive controls. Blood
pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR were unrelated
to TERalb. Responses to acetylcholine were selectively attenuated in metabolic
patients and, on an individual basis, related only to HDL cholesterol levels,
independent of LDL cholesterol, BP, body size, triglycerides, and HOMA-IR
values. No relationship existed between responses to acetylcholine and TERalb.
CONCLUSIONS: Altered systemic capillary permeability characterizes
insulin-resistant hypertensive patients with Metabolic Syndrome. That defect,
which may promote early atherosclerosis development, coexists with blunted
endothelial-mediated vasodilation, indicating a pervasive abnormality of
endothelial function.
DOI: 10.1016/j.atherosclerosis.2003.11.013
PMID: 15019550 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12495442 | 1. BMC Neurosci. 2002 Dec 20;3:20. doi: 10.1186/1471-2202-3-20. Epub 2002 Dec 20.
A role for cryptochromes in sleep regulation.
Wisor JP(1), O'Hara BF, Terao A, Selby CP, Kilduff TS, Sancar A, Edgar DM,
Franken P.
Author information:
(1)Dept of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, CA, USA. [email protected]
BACKGROUND: The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the
generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-)
lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline
conditions as well as under conditions of constant darkness and enforced
wakefulness to determine whether cryptochromes influence sleep regulatory
processes.
RESULTS: Under all three conditions, cry1,2-/- mice exhibit the hallmarks of
high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS
consolidation, and EEG delta power during NREMS). This unexpected phenotype was
associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and
albumin d-binding protein (dbp), which are known to be transcriptionally
inhibited by CRY1,2. To further examine the relationship between circadian genes
and sleep homeostasis, we examined wild type mice and rats following sleep
deprivation and found increased levels of per1,2 mRNA and decreased levels of
dbp mRNA specifically in the cerebral cortex; these changes subsided with
recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and
casein-kinase-1epsilon did not change with sleep deprivation.
CONCLUSIONS: These results indicate that mice lacking cryptochromes are not
simply a genetic model of circadian arrhythmicity in rodents and functionally
implicate cryptochromes in the homeostatic regulation of sleep.
DOI: 10.1186/1471-2202-3-20
PMCID: PMC149230
PMID: 12495442 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21675061 | 1. Anaesth Intensive Care. 2011 May;39(3):418-25. doi:
10.1177/0310057X1103900312.
Myocardial injury in remifentanil-based anaesthesia for off-pump coronary artery
bypass surgery: an equipotent dose of sevoflurane versus propofol.
Kim TY(1), Kim DK, Yoon TG, Lim JA, Woo NS, Chee HK, Shin JK, Song MG, Kim SH.
Author information:
(1)Department of Anaesthesiology and Pain Medicine, Konkuk University School of
Medicine, Seoul, Korea. [email protected]
This randomised controlled trial compared the effect of equipotent anaesthetic
doses of sevoflurane (S group) versus propofol (P group), during
remifentanil-based anaesthesia for off-pump coronary artery bypass surgery, on
myocardial injury. Either sevoflurane or propofol was titrated to maintain
bispectral index values between 40 and 50. In both groups, a targeted
concentration of remifentanil 20 ng x ml(-1) was maintained during anaesthesia.
The concentrations of creatine kinase MB and troponin I were measured before the
start of surgery, on admission to the intensive care unit, and at 12 and 24
hours after intensive care unit admission. The postoperative values of creatine
kinase MB (S group: 15.08 +/- 18.97, 20.78 +/- 20.92, 12.76 +/- 12.82 vs 2.09
+/- 1.54 ng x ml(-1); P group: 10.99 +/- 13.15 27.16 +/- 56.55 11.88 +/- 18.80
vs 1.84 +/- 1.67 ng x ml(-1)) and troponin I (S group: 3.56 +/- 5.19, 566 +/-
7.89, 3.35 +/- 4.55 vs 0.52 +/- 1.90 ng x ml(-1); P group: 2.42 +/- 3.33, 4.11
+/- 6.01, 3.04 +/- 5.31 vs 0.43 +/- 1.28 ng x ml(-1)) were significantly higher
than preoperative values in both groups but there were no significant
differences between the two groups. There were no significant differences in
time to extubation (S group, 476 +/- 284 minutes; P group, 450 +/- 268 minutes)
and intensive care unit length of stay (S group, 2775 +/- 1449 minutes; P group,
2797 +/- 1534 minutes) between the two groups. In conclusion, sevoflurane and
propofol at equipotent doses guided by bispectral index with remifentanil 20 ng
x ml(-1) had similar creatine kinase MB and troponin I values.
DOI: 10.1177/0310057X1103900312
PMID: 21675061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24888775 | 1. Pathol Int. 2014 May;64(5):217-23. doi: 10.1111/pin.12165.
Mucinous breast carcinoma with a lobular neoplasia component: a subset with
aberrant expression of cell adhesion and polarity molecules and lack of
neuroendocrine differentiation.
Jimbo K(1), Tsuda H, Yoshida M, Miyagi-Maeshima A, Sasaki-Katsurada Y, Asaga S,
Hojo T, Kitagawa Y, Kinoshita T.
Author information:
(1)Breast Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
We investigated whether some mucinous carcinomas (MUCs) are associated with
lobular neoplasia (LN) components, and if so, whether this subset has any
distinct biological properties. MUC specimens from 41 patients were stratified
into pure and mixed types. The LN components adjacent to MUC lesions were
examined histopathologically. We also tested immunohistochemically for
E-cadherin, β-catenin, and the neuroendocrine markers chromogranin A and
synaptophysin; and compared results between MUCs with and without LN. Of 41
patients with MUC, LN was detected in 12 patients (29%); LN alone was the
noninvasive component in 8 patients (20%). Decreased E-cadherin and β-catenin
expression in the MUC component was detected in 2 (17%) and 7 (58%) cases,
respectively, of MUC with LN, compared with 0% (P = 0.080) and 21% (P = 0.018)
in MUCs without LN. Neuroendocrine factors were frequently detected in MUCs with
LN (42%) and without LN (52%), but tended to be less frequent in MUCs with only
LN components (25%) than in other MUCs (55%; P = 0.133). MUCs associated with LN
components appear to be a biologically characteristic subset that frequently
shows decreased cell-cell adhesion, cell polarity molecules and lack of
neuroendocrine differentiation.
© 2014 The Authors. Pathology International © 2014 Japanese Society of Pathology
and Wiley Publishing Asia Pty Ltd.
DOI: 10.1111/pin.12165
PMID: 24888775 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10922975 | 1. Diabetes Metab. 2000 Jul;26 Suppl 4:64-6.
Microalbuminuria, endothelial dysfunction and cardiovascular risk.
Feldt-Rasmussen B(1).
Author information:
(1)Nephrological Department, Rigshospitalet, Copenhagen, Danemark. [email protected]
Microalbuminuria was originally considered to be an important new risk factor
for diabetic nephropathy. More recently, it has been convincingly shown that
microalbuminuria is also an independent risk factor for cardiovascular morbidity
and mortality in Type 1 and Type 2 diabetic patients. Even in the non-diabetic
background population, microalbuminuria is a risk factor for cardiovascular
mortality. What is the link between increased loss of albumin in urine and
cardiovascular disease and mortality? As microalbuminuria is apparently
associated with increased universal vascular sieving of albumin in terms of the
transcapillary escape rate of albumin (TER-alb), microalbuminuria may reflect
this universal sieving. The pathophysiology of increased TER-alb is unknown, but
could be caused by haemodynamics or damage to the functional properties of the
vascular wall. A number of studies have provided evidence of endothelial
dysfunction in patients with microalbuminuria, which may be the common link
accounting for the associations mentioned above. In this context, a number of
markers of endothelial cell dysfunction have been found to be increased in
patients with microalbuminuria. In addition, a number of functional in vivo
tests of endothelial dysfunction have been performed in Type 1 and Type 2
diabetic patients as well as in normal controls. Overall, these studies indicate
the existence of a functional vascular dysfunction in Type 1 diabetic patients
and normal controls with microalbuminuria, which may be related to dysfunction
of endothelial cells.
PMID: 10922975 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20364115 | 1. Epigenetics. 2010 Apr;5(3):189-93. doi: 10.4161/epi.5.3.11374. Epub 2010 Apr
1.
DNA methylation in adult stem cells: new insights into self-renewal.
Trowbridge JJ(1), Orkin SH(2).
Author information:
(1)Harvard Medical School.
(2)Howard Hughes Medical Institute.
Methylation of cytosine residues in the context of CpG dinucleotides within
mammalian DNA is an epigenetic modification with profound effects on
transcriptional regulation. A group of enzymes, the DNA methyltransferases
(DNMTs) tightly regulate both the initiation and maintenance of these methyl
marks. Loss of critical components of this enzymatic machinery results in
growth, viability, and differentiation defects in both mice and humans,
supporting the notion that this epigenetic modification is essential for proper
development. Beyond this, DNA methylation also provides a potent epigenetic
mechanism for cellular memory needed to silence repetitive elements and preserve
lineage specificity over repeated cell divisions throughout adulthood. Recent
work highlighting the specialized roles of DNA methylation and
methyltransferases in maintaining adult somatic stem cell function suggests that
further dissection of these mechanisms will shed new light on the complex nature
of self-renewal.
DOI: 10.4161/epi.5.3.11374
PMID: 20364115 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2264817 | 1. Biochem J. 1990 Nov 15;272(1):139-45. doi: 10.1042/bj2720139.
Determination of the critical concentration required for desmin assembly.
Chou RG(1), Stromer MH, Robson RM, Huiatt TW.
Author information:
(1)Muscle Biology Group, Iowa State University, Ames 50011.
The critical concentration required for filament assembly in vitro from highly
purified desmin was determined by both turbidity and centrifugation assays.
Assembly was done in the presence of 2 mM-Ca2+, 2 mM-Mg2+ or 150 mM-Na+ at 2, 22
and 37 degrees C. Similar values for critical concentration were obtained by
both assays. As temperature increased, critical concentration decreased for each
cation. The critical concentration was lowest in the presence of Ca2+ at 2, 22
and 37 degrees C, but was highest in the presence of 150 mM-Na+ at 2 degrees C.
Negative staining showed that supernatants from the centrifugation assays
contained protofilaments, protofibrils and short particles (less than 300 nm),
but pellets contained long filaments (greater than 1 micron) with an average
diameter of 10 nm. As the temperature increased, both the average diameter and
average length of particles in the supernatant increased. Thermodynamic analysis
indicated that hydrophobic interactions were dominant during desmin assembly,
but that ionic interactions might also be involved. Our results demonstrated
that the specific cation and temperature and temperature-cation interactions all
are important in assembly of desmin intermediate filaments.
DOI: 10.1042/bj2720139
PMCID: PMC1149668
PMID: 2264817 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16859531 | 1. Genome Biol. 2006;7(7):R56. doi: 10.1186/gb-2006-7-7-r56.
Shuffling of cis-regulatory elements is a pervasive feature of the vertebrate
lineage.
Sanges R(1), Kalmar E, Claudiani P, D'Amato M, Muller F, Stupka E.
Author information:
(1)Telethon Institute of Genetics and Medicine, Via P, Castellino, 80131 Napoli,
Italy.
BACKGROUND: All vertebrates share a remarkable degree of similarity in their
development as well as in the basic functions of their cells. Despite this,
attempts at unearthing genome-wide regulatory elements conserved throughout the
vertebrate lineage using BLAST-like approaches have thus far detected noncoding
conservation in only a few hundred genes, mostly associated with regulation of
transcription and development.
RESULTS: We used a unique combination of tools to obtain regional global-local
alignments of orthologous loci. This approach takes into account shuffling of
regulatory regions that are likely to occur over evolutionary distances greater
than those separating mammalian genomes. This approach revealed one order of
magnitude more vertebrate conserved elements than was previously reported in
over 2,000 genes, including a high number of genes found in the membrane and
extracellular regions. Our analysis revealed that 72% of the elements identified
have undergone shuffling. We tested the ability of the elements identified to
enhance transcription in zebrafish embryos and compared their activity with a
set of control fragments. We found that more than 80% of the elements tested
were able to enhance transcription significantly, prevalently in a
tissue-restricted manner corresponding to the expression domain of the
neighboring gene.
CONCLUSION: Our work elucidates the importance of shuffling in the detection of
cis-regulatory elements. It also elucidates how similarities across the
vertebrate lineage, which go well beyond development, can be explained not only
within the realm of coding genes but also in that of the sequences that
ultimately govern their expression.
DOI: 10.1186/gb-2006-7-7-r56
PMCID: PMC1779573
PMID: 16859531 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19073165 | 1. Dev Biol. 2009 Mar 15;327(2):526-40. doi: 10.1016/j.ydbio.2008.10.044. Epub
2008 Nov 12.
Systematic human/zebrafish comparative identification of cis-regulatory activity
around vertebrate developmental transcription factor genes.
Navratilova P(1), Fredman D, Hawkins TA, Turner K, Lenhard B, Becker TS.
Author information:
(1)Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen,
Norway.
Pan-vertebrate developmental cis-regulatory elements are discernible as highly
conserved noncoding elements (HCNEs) and are often dispersed over large areas
around the pleiotropic genes whose expression they control. On the loci of two
developmental transcription factor genes, SOX3 and PAX6, we demonstrate that
HCNEs conserved between human and zebrafish can be systematically and reliably
tested for their regulatory function in multiple stable transgenes in zebrafish,
and their genomic reach estimated with confidence using synteny conservation and
HCNE density along these loci. HCNEs of both human and zebrafish function as
specific developmental enhancers in zebrafish. We show that human HCNEs result
in expression patterns in zebrafish equivalent to those in mouse, establishing
zebrafish as a suitable model for large-scale testing of human developmental
enhancers. Orthologous human and zebrafish enhancers underwent functional
evolution within their sequence and often directed related but non-identical
expression patterns. Despite an evolutionary distance of 450 million years, one
pax6 HCNE drove expression in identical areas when comparing zebrafish vs. human
HCNEs. HCNEs from the same area often drive overlapping patterns, suggesting
that multiple regulatory inputs are required to achieve robust and precise
complex expression patterns exhibited by developmental genes.
DOI: 10.1016/j.ydbio.2008.10.044
PMID: 19073165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19656809 | 1. J Biochem. 2009 Nov;146(5):627-31. doi: 10.1093/jb/mvp121. Epub 2009 Aug 5.
Vimentin intermediate filaments as a template for silica nanotube preparation.
Gohara R(1), Liu D, Nakashima K, Takasaki Y, Ando S.
Author information:
(1)Department of Biomolecular Sciences, Faculty of Medicine, Saga University,
Nabeshima, Saga 849-8501, Japan.
Organic compounds are used as templates to regulate the morphology of inorganic
nanostructures. In the present study, we used intermediate filaments (IFs), the
major cytoskeleton component of most eukaryotic cells, as a template for hollow
silica nanotube preparation. Sol-gel polymerization of tetraethoxysilane
proceeded preferentially on the surface of IFs assembled from vimentin protein
in vitro, resulting in silica-coated fibres. After removing IFs by calcination,
electron microscopy revealed hollow silica nanotubes several micrometers long,
with outer diameters of 35-55 nm and an average inner diameter of 10 nm
(comparable to that of IFs). Furthermore, the silica nanotubes exhibited a
gnarled surface structure with an 18-26 nm repeating pattern (comparable to the
21-nm beading pattern along IFs). Thus, the characteristic morphology of IFs
were well replicated into hollow silica nanotubes, suggesting that IFs maybe
useful as an organic template.
DOI: 10.1093/jb/mvp121
PMID: 19656809 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25532001 | 1. J Gastrointestin Liver Dis. 2014 Dec;23(4):419-24. doi:
10.15403/jgld.2014.1121.234.3ca.
A comparison of three chromogranin A assays in patients with neuroendocrine
tumours.
Brehm Hoej L(1), Parkner T(2), Soendersoe Knudsen C(2), Grønbaek H(3).
Author information:
(1)Department of Medicine V (Hepatology and Gastroenterology), Aarhus University
Hospital, Aarhus, Denmark. [email protected].
(2)Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus,
Denmark.
(3)Department of Medicine V (Hepatology and Gastroenterology), Aarhus University
Hospital, Aarhus, Denmark.
BACKGROUND AND AIMS: Chromogranin A (CgA) is the most important general tumour
marker used in the diagnosis and follow-up of patients with neuroendocrine
tumours (NET). Chromogranin A assays may have different sensitivities, which is
of importance for the clinical diagnosis and handling of NET patients. The aim
of this study was to compare the clinical sensitivities of three different CgA
assays in NET patients.
METHODS: We measured CgA level in 42 NET patients (male/female: 23/19, median
age: 63 years, range 29-85 years). Twenty-five patients had liver metastases,
eight had local disease, and nine were disease free after surgery. We studied an
in-house RIA: RH RIA assay (Rigshospitalet, Copenhagen, Denmark); NEOLISATM
(Euro Diagnostica, Malmö, Sweden) and EURIA CgA RIA (Euro Diagnostica, Malmö,
Sweden).
RESULTS: The RH RIA assay showed a clinical sensitivity of 97%, while the
NEOLISA and EURIA assays both showed similar clinical sensitivities of 79%.
Patients with liver metastases had significantly higher CgA levels compared to
disease free patients by all three assays (P<0.001), but only the RH RIA assay
was able to discriminate between patients with liver metastases and with
regional disease (P<0.01).
CONCLUSION: Chromogranin A measurements are significantly assay-dependent and
caution should be applied in the interpretation of CgA measurement for
assessment of NET status. The in-house RH RIA assay was better at predicting NET
status than the NEOLISA and EURIA assays.
DOI: 10.15403/jgld.2014.1121.234.3ca
PMID: 25532001 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18922972 | 1. Mol Cancer Res. 2008 Oct;6(10):1567-74. doi: 10.1158/1541-7786.MCR-08-0234.
Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically
silenced genes in primary human pituitary tumors.
Dudley KJ(1), Revill K, Whitby P, Clayton RN, Farrell WE.
Author information:
(1)Institute of Science and Technology in Medicine, Keele University, Hartshill,
Stoke on Trent, United Kingdom.
DNA methylation at promoter CpG islands (CGI) is an epigenetic modification
associated with inappropriate gene silencing in multiple tumor types. In the
absence of a human pituitary tumor cell line, small interfering RNA-mediated
knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine
5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20.
Sustained knockdown induced reexpression of the fully methylated and normally
imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite
restriction analysis (COBRA) revealed that reexpression of Nnat was associated
with partial CGI demethylation, which was also observed at the H19
differentially methylated region. Subsequent genome-wide microarray analysis
identified 91 genes that were significantly differentially expressed in Dnmt1
knockdown cells (10% false discovery rate). The analysis showed that genes
associated with the induction of apoptosis, signal transduction, and
developmental processes were significantly overrepresented in this list (P <
0.05). Following validation by reverse transcription-PCR and detection of
inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and
S100A10) were analyzed in primary human pituitary tumors, each displaying
significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For
two of these genes, NNAT and S100A10, decreased expression was associated with
increased promoter CGI methylation. Induced expression of Nnat in stable
transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is
the first report of array-based "epigenetic unmasking" in combination with Dnmt1
knockdown and reveals the potential of this strategy toward identifying genes
silenced by epigenetic mechanisms across species boundaries.
DOI: 10.1158/1541-7786.MCR-08-0234
PMID: 18922972 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17396267 | 1. J Math Biol. 2007 Sep;55(3):299-330. doi: 10.1007/s00285-007-0085-7. Epub 2007
Mar 30.
Approximating genealogies for partially linked neutral loci under a selective
sweep.
Pfaffelhuber P(1), Studeny A.
Author information:
(1)Ludwig-Maximilian University Munich, Munich, Germany. [email protected]
Consider a genetic locus carrying a strongly beneficial allele which has
recently fixed in a large population. As strongly beneficial alleles fix
quickly, sequence diversity at partially linked neutral loci is reduced. This
phenomenon is known as a selective sweep. The fixation of the beneficial allele
not only affects sequence diversity at single neutral loci but also the joint
allele distribution of several partially linked neutral loci. This distribution
can be studied using the ancestral recombination graph for samples of partially
linked neutral loci during the selective sweep. To approximate this graph, we
extend recent work by Etheridge et al. (Ann Appl Probab 16:685-729, 2006) and
Schweinsberg and Durrett (Ann Appl Probab 15:1591-1651, 2005) using a marked
Yule tree for the genealogy at a single neutral locus linked to a strongly
beneficial one. We focus on joint genealogies at two partially linked neutral
loci in the case of large selection coefficients alpha and recombination rates
rho = theta(alpha/log alpha) between loci. Our approach leads to a full
description of the genealogy with accuracy of theta((log alpha)(-2)) in
probability. As an application, we derive the expectation of Lewontin's D as a
measure for non-random association of alleles.
DOI: 10.1007/s00285-007-0085-7
PMID: 17396267 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23029374 | 1. PLoS One. 2012;7(9):e46036. doi: 10.1371/journal.pone.0046036. Epub 2012 Sep
28.
Implication of DNA demethylation and bivalent histone modification for selective
gene regulation in mouse primordial germ cells.
Mochizuki K(1), Tachibana M, Saitou M, Tokitake Y, Matsui Y.
Author information:
(1)Cell Resource Center for Biomedical Research, Institute of Development, Aging
and Cancer, Tohoku University, Sendai, Japan.
Primordial germ cells (PGCs) sequentially induce specific genes required for
their development. We focused on epigenetic changes that regulate PGC-specific
gene expression. mil-1, Blimp1, and Stella are preferentially expressed in PGCs,
and their expression is upregulated during PGC differentiation. Here, we first
determined DNA methylation status of mil-1, Blimp1, and Stella regulatory
regions in epiblast and in PGCs, and found that they were hypomethylated in
differentiating PGCs after E9.0, in which those genes were highly expressed. We
used siRNA to inhibit a maintenance DNA methyltransferase, Dnmt1, in embryonic
stem (ES) cells and found that the flanking regions of all three genes became
hypomethylated and that expression of each gene increased 1.5- to 3-fold. In
addition, we also found 1.5- to 5-fold increase of the PGC genes in the PGCLCs
(PGC-like cells) induced form ES cells by knockdown of Dnmt1. We also obtained
evidence showing that methylation of the regulatory region of mil-1 resulted in
2.5-fold decrease in expression in a reporter assay. Together, these results
suggested that DNA demethylation does not play a major role on initial
activation of the PGC genes in the nascent PGCs but contributed to enhancement
of their expression in PGCs after E9.0. However, we also found that repression
of representative somatic genes, Hoxa1 and Hoxb1, and a tissue-specific gene,
Gfap, in PGCs was not dependent on DNA methylation; their flanking regions were
hypomethylated, but their expression was not observed in PGCs at E13.5. Their
promoter regions showed the bivalent histone modification in PGCs, that may be
involved in repression of their expression. Our results indicated that
epigenetic status of PGC genes and of somatic genes in PGCs were distinct, and
suggested contribution of epigenetic mechanisms in regulation of the expression
of a specific gene set in PGCs.
DOI: 10.1371/journal.pone.0046036
PMCID: PMC3461056
PMID: 23029374 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21219847 | 1. Dan Med Bull. 2010 Jun;57(6):B4145.
Ambulatory blood pressure, endothelial perturbation, and microvascular
complications in type 2 diabetes.
Knudsen ST(1).
Author information:
(1)Medical Department, Regional Hospital Silkeborg, Falkevej 1-3, 8600
Silkeborg. Denmark. [email protected]
Diabetic vascular complications constitute leading causes of blindness, renal
failure, and cardiovascular morbidity and mortality world-wide. We studied
haemodynamic and structural abnormalities associated with the development of
microvascular complications and evaluated the effect of intervention with
antihypertensive agents on these risk factors and complications in type 2
diabetic patients (T2DM). Retinal thickness, urinary albumin excretion rate, and
transcapillary escape rate of albumin were strongly associated in T2DM patients
with maculopathy, suggesting that macular oedema is a marker of generalised
vascular hyperpermeability in T2DM. Plasma from T2DM patients with maculopathy
stimulated the expression of E-selectin in cultured endothelial cells. Reduced
nocturnal blood pressure decline ("non-dipping") and elevated pulse pressure
(PP) were associated with micro- and macrovascular complications and predicted
progression of nephropathy in T2DM subjects. Non-dipping and elevated PP were
associated with increased plasma levels of markers of endothelial activation in
T2DM patients, suggesting that endothelial perturbation could represent a
pathophysiological link between these haemodynamic risk factors and the
development of vascular complications in T2DM. 4 months treatment with losartan
50 mg o.d. did not ameliorate macular oedema in T2DM patients with maculopathy.
12 months dual blockade of the renin-angiotensin system with candesartan and
lisinopril reduced ambulatory PP levels compared with high-dose lisinopril
monotherapy in hypertensive T2DM subjects.
PMID: 21219847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22342390 | 1. Nutrition. 2012 Jul;28(7-8):767-72. doi: 10.1016/j.nut.2011.11.008. Epub 2012
Feb 17.
Effects of coenzyme Q10 supplementation on inflammatory markers
(high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in
patients with coronary artery disease.
Lee BJ(1), Huang YC, Chen SJ, Lin PT.
Author information:
(1)School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
OBJECTIVE: The purpose of this study was to investigate the effects of coenzyme
Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein
[hs-CRP], interleukin-6 [IL-6], and homocysteine) in patients with coronary
artery disease (CAD).
METHODS: Patients with CAD (n = 51) were randomly assigned to a placebo group (n
= 14) or one of two coenzyme Q10-supplemented groups (60 mg/d, Q10-60 group, n =
19; 150 mg/d, Q10-150 group, n = 18). The intervention was administered for 12
wk. Plasma coenzyme Q10 concentration, inflammatory markers (hs-CRP, IL-6, and
homocysteine), malondialdehyde, and superoxide dismutase activities were
measured.
RESULTS: Forty subjects with CAD completed the intervention study. The plasma
coenzyme Q10 concentration increased significantly in the Q10-60 and Q10-150
groups (P < 0.01). After 12 wk of intervention, the inflammatory marker IL-6 (P
= 0.03) was decreased significantly in the Q10-150 group. Subjects in the
Q10-150 group had significantly lower malondialdehyde levels and those in the
Q10-60 (P = 0.05) and Q10-150 (P = 0.06) groups had greater superoxide dismutase
activities. Plasma coenzyme Q10 was inversely correlated with hs-CRP (r = -0.20,
P = 0.07) and IL-6 (r = -0.25, P = 0.03) at baseline. After supplementation,
plasma coenzyme Q10 was significantly correlated with malondialdehyde (r =
-0.35, P < 0.01) and superoxide dismutase activities (r = 0.52, P < 0.01).
However, there was no correlation between coenzyme Q10 and homocysteine.
CONCLUSION: Coenzyme Q10 supplementation at a dosage of 150 mg appears to
decrease the inflammatory marker IL-6 in patients with CAD.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nut.2011.11.008
PMID: 22342390 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24897131 | 1. Scand J Gastroenterol. 2014 Aug;49(8):942-9. doi:
10.3109/00365521.2014.920910. Epub 2014 Jun 4.
Chromogranin A as a biomarker of disease activity and biologic therapy in
inflammatory bowel disease: a prospective observational study.
Zissimopoulos A(1), Vradelis S, Konialis M, Chadolias D, Bampali A,
Constantinidis T, Efremidou E, Kouklakis G.
Author information:
(1)Deartment of Nuclear Medicine, Democritus University of Thrace ,
Alexandroupolis, 68100 , Greece.
Comment in
Scand J Gastroenterol. 2014 Dec;49(12):1501-2. doi:
10.3109/00365521.2014.953573.
Scand J Gastroenterol. 2014 Nov;49(11):1397. doi:
10.3109/00365521.2014.959041.
OBJECTIVE: To access the correlation of Chromogranin A (CgA) with inflammatory
bowel disease (IBD) activity and responsiveness to medical therapy.
MATERIAL AND METHODS: A prospective observational study was conducted in 56
patients with moderate ulcerative colitis (UC) or Crohn's disease (CD) (UC, n =
29, CD, n = 27), 17 patients with irritable bowel syndrome and predominant
diarrhea (IBS-D) and 40 healthy volunteers. IBD patients were treated by
biologics (infliximab or adalimumab) or conventional agents (aminosalicylates,
thiopurines or methotrexate and steroids) and were classified according to their
treatment in two groups. Serum CgA was measured at baseline and 4-week
posttreatment period.
RESULTS: Serum CgA was significantly higher in IBD patients than in those with
IBS-D or healthy volunteers (p < 0.01). Furthermore, serum CgA was markedly
increased in CD patients than in UC patients (p < 0.01). CgA value was
significantly reduced in 'biologic' group (24 IBD patients, UC, n = 15, CD, n =
9) at 4-week posttreatment period (p < 0.01), while 18/24 (72%) patients were
already in remission during that time. In contrast, CgA value was significantly
increased in the 'conventional' treatment group (32 IBD patients, UC, n = 14,
CD, n = 18) between the two visits (p < 0.01), although 22/32 (69%) patients
were in remission during the 4-week posttreatment period.
CONCLUSION: CgA appears to be a reliable marker of disease activity in IBD
patients and especially in those who received biologic therapy. IBS-D patients
presented normal CgA values.
DOI: 10.3109/00365521.2014.920910
PMID: 24897131 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10575394 | 1. Arch Fam Med. 1999 Nov-Dec;8(6):537-42. doi: 10.1001/archfami.8.6.537.
The role of vitamin E in the prevention of heart disease.
Emmert DH(1), Kirchner JT.
Author information:
(1)Department of Family and Community Medicine, Lancaster General Hospital, Pa.,
USA. [email protected]
Data from the 1970s first suggested that vitamin E may be effective in
decreasing mortality from cardiovascular disease. As the understanding of the
antioxidant effect of this vitamin evolved, researchers began to further study
the biologic effects of vitamin E. In vitro studies have shown vitamin E to have
several potentially cardioprotective effects, including antagonizing the
oxidation of low-density lipoproteins, inhibiting platelet aggregation and
adhesion, preventing smooth muscle proliferation, and preserving normal coronary
dilation. Several prospective studies, including the US Nurses' Health Study and
the US Health Professionals' Follow-up Study, found a 34% and 39% reduction,
respectively, in the risk of having a cardiac event for those taking vitamin E
supplements. The Iowa Women's Health Study found a 47% reduction in cardiac
mortality. Results of randomized, controlled clinical trials have not found
consistent benefit, however. The best known of these trials, the Cambridge Heart
Antioxidant Study, found a 47% reduction in fatal and nonfatal myocardial
infarction in patients with proven coronary atherosclerosis who were given 400
or 800 IU of vitamin E daily. There was, however, no effect on mortality. While
emerging and promising data suggest the potential benefit of vitamin E for
high-risk cardiac patients, physicians should be alert to the results of
randomized, controlled clinical trials already in progress.
DOI: 10.1001/archfami.8.6.537
PMID: 10575394 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11944023 | 1. J Lab Clin Med. 2002 Mar;139(3):133-9. doi: 10.1067/mlc.2002.121450.
Antioxidant nutrient supplementation and brachial reactivity in patients with
coronary artery disease.
McKechnie R(1), Rubenfire M, Mosca L.
Author information:
(1)Department of Internal Medicine, Division of Cardiology, University of
Michigan Medical Center, Ann Arbor, MI, USA.
Epidemiologic studies have shown a correlation between antioxidant intake and
coronary artery disease (CAD); however, the results of clinical trials have been
inconsistent. We evaluated the effect of combined antioxidant supplementation on
endothelial function and its correlation with change in low-density lipoprotein
cholesterol (LDLC) oxidation in patients with established CAD. In a
double-blind, placebo-controlled 12-week trial, 18 nonsmoking, nondiabetic
patients (mean age 62.4 +/- 8.1 years) were randomized to receive placebo or
antioxidant supplementation consisting of (a) 400 IU of vitamin E, 500 mg of
vitamin C, and 12 mg of beta-carotene; or (b) 800 IU of vitamin E, 1000 mg of
vitamin C, and 24 mg of beta-carotene daily. Endothelial function was evaluated
on the basis of percent and absolute changes in brachial artery diameter in
response to reactive hyperemia induced by occlusion-release. Baseline and
12-week values of LDL oxidation (measured on the basis of lag phase),
endothelial function, dietary composition, serum antioxidants, and lipids were
measured. We noted a significant between-group difference at 12 weeks for change
in plasma concentrations of alpha-tocopherol, vitamin C, and beta-carotene
between the placebo and antioxidant groups (p <.05). Both placebo and treatment
groups demonstrated a significant improvement in lag phase; however, the
treatment group achieved a greater, although nonsignificant, magnitude of change
compared with the placebo group (181.3 +/- 177.8 minutes vs 80.6 +/- 63.0
minutes, P =.06). Within-group change in brachial reactivity from baseline to
follow-up in the treatment group did not reach statistical significance (1.7%
+/- 3.2% and 0.07 mm +/- 0.13 mm, P =.08 and P =.09, respectively), whereas an
improved change in brachial reactivity was observed in the placebo group (2.2%
+/- 1.9%, 0.09 mm +/- 0.06 mm, P <.05). No significant correlation was found
between change in lag phase and change in endothelial function. On adjustment
for confounders, antioxidant supplementation was found not to be a significant
predictor of brachial reactivity. We conclude that antioxidant supplementation
did not significantly alter brachial reactivity, despite significantly increased
plasma levels of antioxidants and improved lag phase. These data should be
confirmed in larger-scale trials and examined in studies evaluating individual
dietary antioxidant supplementation.
DOI: 10.1067/mlc.2002.121450
PMID: 11944023 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2951101 | 1. Diabet Med. 1985 Sep;2(5):400-4. doi: 10.1111/j.1464-5491.1985.tb00663.x.
Insulin oedema and its clinical significance: metabolic studies in three cases.
Wheatley T, Edwards OM.
Three patients with insulin-dependent diabetes mellitus are described in whom
generalized oedema and weight gain followed the administration of excessive
monocomponent insulins, in two cases associated with symptomatic hypoglycaemia.
Serial measurements of plasma volume and transcapillary escape rate of albumin
(TERA) using 125I-labelled albumin, serum colloid osmotic pressure (COP) using a
membrane colloid osmometer, packed cell volume (PCV), and serum proteins, showed
that oedema was associated with an increased plasma volume and TERA, while serum
albumin and total protein concentration and serum COP were reduced. A reduction
in daily insulin dose abolished hypoglycaemia and resulted in weight loss,
natriuresis, diuresis, a reduction in plasma volume and TERA, and an increase in
serum albumin, total protein, and COP. Strict metabolic control in previously
poorly controlled patients may cause insulin-induced increments in plasma volume
and albumin escape rate.
DOI: 10.1111/j.1464-5491.1985.tb00663.x
PMID: 2951101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20140188 | 1. PLoS Genet. 2010 Feb 5;6(2):e1000794. doi: 10.1371/journal.pgen.1000794.
Genomic hotspots for adaptation: the population genetics of Müllerian mimicry in
the Heliconius melpomene clade.
Baxter SW(1), Nadeau NJ, Maroja LS, Wilkinson P, Counterman BA, Dawson A,
Beltran M, Perez-Espona S, Chamberlain N, Ferguson L, Clark R, Davidson C,
Glithero R, Mallet J, McMillan WO, Kronforst M, Joron M, Ffrench-Constant RH,
Jiggins CD.
Author information:
(1)Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
Comment in
PLoS Genet. 6:e1000796.
PLoS Genet. 6:e1000822.
Wing patterning in Heliconius butterflies is a longstanding example of both
Müllerian mimicry and phenotypic radiation under strong natural selection. The
loci controlling such patterns are "hotspots" for adaptive evolution with great
allelic diversity across different species in the genus. We characterise
nucleotide variation, genotype-by-phenotype associations, linkage
disequilibrium, and candidate gene expression at two loci and across multiple
hybrid zones in Heliconius melpomene and relatives. Alleles at HmB control the
presence or absence of the red forewing band, while alleles at HmYb control the
yellow hindwing bar. Across HmYb two regions, separated by approximately 100 kb,
show significant genotype-by-phenotype associations that are replicated across
independent hybrid zones. In contrast, at HmB a single peak of association
indicates the likely position of functional sites at three genes, encoding a
kinesin, a G-protein coupled receptor, and an mRNA splicing factor. At both HmYb
and HmB there is evidence for enhanced linkage disequilibrium (LD) between
associated sites separated by up to 14 kb, suggesting that multiple sites are
under selection. However, there was no evidence for reduced variation or
deviations from neutrality that might indicate a recent selective sweep,
consistent with these alleles being relatively old. Of the three genes showing
an association with the HmB locus, the kinesin shows differences in wing disc
expression between races that are replicated in the co-mimic, Heliconius erato,
providing striking evidence for parallel changes in gene expression between
Müllerian co-mimics. Wing patterning loci in Heliconius melpomene therefore show
a haplotype structure maintained by selection, but no evidence for a recent
selective sweep. The complex genetic pattern contrasts with the simple genetic
basis of many adaptive traits studied previously, but may provide a better model
for most adaptation in natural populations that has arisen over millions rather
than tens of years.
DOI: 10.1371/journal.pgen.1000794
PMCID: PMC2816687
PMID: 20140188 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/10812586 | 1. Nutr Metab Cardiovasc Dis. 2000 Feb;10(1):38-44.
Dietary antioxidants for cardiovascular prevention.
Giugliano D(1).
Author information:
(1)Dipartimento di Gerontologia, Geriatria e Malattie del Metabolismo, Seconda
Università di Napoli, Italy.
The generation of reactive oxygen species (ROS) is associated with life in
aerobic conditions. ROS are thought to be implicated in the pathogenesis of
various human diseases since they are capable of damaging biological
macromolecules such as DNA, carbohydrates and proteins. The organism maintains
defense against ROS, including enzymes and low molecular-weight antioxidants. An
important source of antioxidants is diet which contains numerous compounds
exhibiting antioxidant activity. A shortage of antioxidants in the diet might
promote coronary heart disease through accumulation of oxidized LDL in
macrophages. However, antioxidants may also influence endothelial functions,
smooth muscle cell proliferation, thrombosis and plaque rupture. Consumption of
fruits and vegetables, olive oil, red wine and tea is inversely correlated with
heart disease rates. These foods are particularly rich in natural antioxidant
nutrients, including ascorbate (vitamin C), the tocopherols (vitamin E) and
carotenoids. More than 600 naturally occurring carotenoids have been identified.
These compounds are plant pigments that provide the bright color of various
fruits and vegetables; lycopene, which gives tomatoes their red color, is under
active research. Flavonoids are > 4,000 naturally occurring substances which
provide color, texture and taste for plant foods. As free radical scavengers,
flavonoids inhibit lipid peroxidation, promote vascular relaxation and help
prevent atherosclerosis. A sufficient supply with antioxidants from diet might
help prevent or delay the occurrence of pathological changes associated with
oxidative stress. When diet fails to meet the antioxidant requirement, dietary
supplements might be indicated. The recently coined term nutriceuticals
describes a variety of nonprescription products that are used to enhance health.
The best known are vitamin E, vitamin C, carotenoids, coenzyme Q10, flavonoids
and the amino acid L-arginine. Rigorous clinical trials, particularly among
high-risk groups, are needed before they can be recommended routinely to
patients.
PMID: 10812586 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23837869 | 1. BMC Mol Biol. 2013 Jul 9;14:15. doi: 10.1186/1471-2199-14-15.
Loss of CARM1 is linked to reduced HuR function in replicative senescence.
Pang L(1), Tian H, Chang N, Yi J, Xue L, Jiang B, Gorospe M, Zhang X, Wang W.
Author information:
(1)Department of Biochemistry and Molecular Biology, Peking University health
Science Center, 38 Xueyuan Road, Beijing 100191, P. R. China.
BACKGROUND: The co-activator-associated arginine methyltransferase 1 (CARM1)
catalyzes the methylation of HuR. However, the functional impact of this
modification is not fully understood. Here, we investigated the influence of HuR
methylation by CARM1 upon the turnover of HuR target mRNAs encoding
senescence-regulatory proteins.
RESULTS: Changing the methylation status of HuR in HeLa cells by either
silencing CARM1 or mutating the major methylation site (R217K) greatly
diminished the effect of HuR in regulating the turnover of mRNAs encoding cyclin
A, cyclin B1, c-fos, SIRT1, and p16. Although knockdown of CARM1 or HuR
individually influenced the expression of cyclin A, cyclin B1, c-fos, SIRT1, and
p16, joint knockdown of both CARM1 and HuR did not show further effect.
Methylation by CARM1 enhanced the association of HuR with the 3'UTR of p16 mRNA,
but not with the 3'UTR of cyclin A, cyclin B1, c-fos, or SIRT1 mRNAs. In
senescent human diploid fibroblasts (HDFs), reduced CARM1 was accompanied by
reduced HuR methylation. In addition, knockdown of CARM1 or mutation of the
major methylation site of HuR in HDF markedly impaired the ability of HuR to
regulate the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16 as well to
maintain a proliferative phenotype.
CONCLUSION: CARM1 represses replicative senescence by methylating HuR and
thereby enhancing HuR's ability to regulate the turnover of cyclin A, cyclin B1,
c-fos, SIRT1, and p16 mRNAs.
DOI: 10.1186/1471-2199-14-15
PMCID: PMC3718661
PMID: 23837869 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25099181 | 1. BMC Endocr Disord. 2014 Aug 7;14:64. doi: 10.1186/1472-6823-14-64.
Chromogranin A is a reliable serum diagnostic biomarker for pancreatic
neuroendocrine tumors but not for insulinomas.
Qiao XW, Qiu L, Chen YJ(1), Meng CT, Sun Z, Bai CM, Zhao DC, Zhang TP, Zhao YP,
Song YL, Wang YH, Chen J, Lu CM.
Author information:
(1)Department of Gastroenterology, Peking Union Medical College Hospital, Peking
Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730,
People's Republic of China. [email protected].
BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors.
Chromogranin A (CgA) was considered as the most practical and useful serum tumor
marker in PNET patients. But peripheral blood levels of CgA are not routinely
tested in Chinese patients with PNETs. This study was to assess the diagnostic
value of CgA in Chinese patients with PNETs especially in patients with
insulinomas.
METHODS: Eighty-nine patients with PNETs including 57 insulinomas and 32
non-insulinoma PNETs as well as 86 healthy participants were enrolled in this
study between September 2003 and June 2013. Serum levels of CgA were measured by
ELISA method. Expression of CgA protein was detected in 26 PNET tissues
including 14 insulinomas by immunohistochemical staining.
RESULTS: Serum levels of CgA in 89 PNET patients were significantly higher than
that in healthy controls (P = 7.2 × 10-9). Serum levels of CgA in 57 patients
with insulinomas (median 64.8 ng/ml, range 25-164) were slightly higher than the
levels in healthy controls (median 53.4 ng/ml, range 39-94) but much lower than
the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range
27-9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with
insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml
distinguished patients with insulinomas from healthy controls but its
sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA
values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy
controls, and the sensitivity and specificity were 65.6% and 91.9%,
respectively. Except for two insulinomas with negative staining of CgA, 12
insulinoma tissues showed positive staining of CgA.
CONCLUSION: CgA is a reliable serum diagnostic biomarker for PNETs but not for
insulinomas.
DOI: 10.1186/1472-6823-14-64
PMCID: PMC4130880
PMID: 25099181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12069675 | 1. JAMA. 2002 Jun 19;287(23):3116-26. doi: 10.1001/jama.287.23.3116.
Vitamins for chronic disease prevention in adults: scientific review.
Fairfield KM(1), Fletcher RH.
Author information:
(1)Division of General Medicine and Primary Care, Beth Israel Deaconess Medical
Center and Channing Laboratory, Department of Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA, USA.
[email protected]
Erratum in
JAMA 2002 Oct 9;288(14):1720.
CONTEXT: Although vitamin deficiency is encountered infrequently in developed
countries, inadequate intake of several vitamins is associated with chronic
disease.
OBJECTIVE: To review the clinically important vitamins with regard to their
biological effects, food sources, deficiency syndromes, potential for toxicity,
and relationship to chronic disease.
DATA SOURCES AND STUDY SELECTION: We searched MEDLINE for English-language
articles about vitamins in relation to chronic diseases and their references
published from 1966 through January 11, 2002.
DATA EXTRACTION: We reviewed articles jointly for the most clinically important
information, emphasizing randomized trials where available.
DATA SYNTHESIS: Our review of 9 vitamins showed that elderly people, vegans,
alcohol-dependent individuals, and patients with malabsorption are at higher
risk of inadequate intake or absorption of several vitamins. Excessive doses of
vitamin A during early pregnancy and fat-soluble vitamins taken anytime may
result in adverse outcomes. Inadequate folate status is associated with neural
tube defect and some cancers. Folate and vitamins B(6) and B(12) are required
for homocysteine metabolism and are associated with coronary heart disease risk.
Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is
associated with decreased occurrence of fractures when taken with calcium.
CONCLUSIONS: Some groups of patients are at higher risk for vitamin deficiency
and suboptimal vitamin status. Many physicians may be unaware of common food
sources of vitamins or unsure which vitamins they should recommend for their
patients. Vitamin excess is possible with supplementation, particularly for
fat-soluble vitamins. Inadequate intake of several vitamins has been linked to
chronic diseases, including coronary heart disease, cancer, and osteoporosis
DOI: 10.1001/jama.287.23.3116
PMID: 12069675 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25177680 | 1. Front Chem. 2014 Aug 14;2:64. doi: 10.3389/fchem.2014.00064. eCollection 2014.
The surging role of Chromogranin A in cardiovascular homeostasis.
Tota B(1), Angelone T(1), Cerra MC(1).
Author information:
(1)Department of Biology, Ecology and Earth Sciences, University of Calabria
Arcavacata di Rende (CS), Italy.
Together with Chromogranin B and Secretogranins, Chromogranin A (CGA) is stored
in secretory (chromaffin) granules of the diffuse neuroendocrine system and
released with noradrenalin and adrenalin. Co-stored within the granule together
with neuropeptideY, cardiac natriuretic peptide hormones, several prohormones
and their proteolytic enzymes, CGA is a multifunctional protein and a major
marker of the sympatho-adrenal neuroendocrine activity. Due to its partial
processing to several biologically active peptides, CGA appears an important
pro-hormone implicated in relevant modulatory actions on endocrine,
cardiovascular, metabolic, and immune systems through both direct and indirect
sympatho-adrenergic interactions. As a part of this scenario, we here illustrate
the emerging role exerted by the full-length CGA and its three derived
fragments, i.e., Vasostatin 1, catestatin and serpinin, in the control of
circulatory homeostasis with particular emphasis on their cardio-vascular
actions under both physiological and physio-pathological conditions. The
Vasostatin 1- and catestatin-induced cardiodepressive influences are achieved
through anti-beta-adrenergic-NO-cGMP signaling, while serpinin acts like
beta1-adrenergic agonist through AD-cAMP-independent NO signaling. On the whole,
these actions contribute to widen our knowledge regarding the
sympatho-chromaffin control of the cardiovascular system and its highly
integrated "whip-brake" networks.
DOI: 10.3389/fchem.2014.00064
PMCID: PMC4132265
PMID: 25177680 |
http://www.ncbi.nlm.nih.gov/pubmed/23275783 | 1. Case Rep Neurol. 2012 Sep;4(3):212-5. doi: 10.1159/000345847. Epub 2012 Sep
27.
A case of fisher-bickerstaff syndrome overlapped by guillain-barré syndrome.
Fujii D(1), Manabe Y, Takahasi Y, Narai H, Omori N, Kusunoki S, Abe K.
Author information:
(1)Department of Neurology, National Hospital Organization Okayama Medical
Center, Okayama, Japan.
We report a 72-year-old woman with overlapping Miller Fisher syndrome (MFS),
Guillain-Barré syndrome (GBS) and Bickerstaff's brainstem encephalitis (BBE).
She developed diplopia and unsteady gait a week after an upper respiratory
infection on day 1. She had weakness of both upper limbs on day 3 and became
drowsy, and her respiratory status worsened on day 5. Neurologic examination
revealed ophthalmoplegia, ataxia, symmetrical weakness, areflexia, and
consciousness disturbance. We diagnosed her with MFS on day 1, GBS on day 3 and
overlapping BBE on day 5. She underwent immunoadsorption therapy and two courses
of intravenous immunoglobulin therapy. Ten months after onset, her symptoms had
fully recovered. Anti-GM1 IgG, GD1a IgG, GQ1b IgG, and GT1a IgG antibodies were
positive. Our case supports the notion that MFS, GBS, and BBE are all part of a
continuous clinical spectrum, which is an antibody-mediated process.
DOI: 10.1159/000345847
PMCID: PMC3531931
PMID: 23275783 |
http://www.ncbi.nlm.nih.gov/pubmed/25294372 | 1. Hum Pathol. 2014 Dec;45(12):2463-70. doi: 10.1016/j.humpath.2014.08.013. Epub
2014 Sep 6.
Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative
immunohistochemical study of 46 cases.
Weissferdt A(1), Kalhor N(2), Liu H(3), Rodriguez J(3), Fujimoto J(3), Tang
X(3), Wistuba II(3), Moran CA(2).
Author information:
(1)Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030.
Electronic address: [email protected].
(2)Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030.
(3)Department of Translational Molecular Pathology, MD Anderson Cancer Center,
Houston, TX 77030.
Twenty-two paragangliomas from different anatomical sites and 24 thymic
neuroendocrine carcinomas (carcinoid tumors) were analyzed for traditional and
novel immunohistochemical markers. In the paraganglioma group, there were 8 men
and 14 women between the ages of 23 and 79 years (mean, 46 years). Their
symptoms depended on the location of the tumor and included neck swelling and
Horner syndrome for neck tumors, whereas abdominal and chest pain was present in
tumors of the abdomen and mediastinum, respectively. One patient had Carney
triad. In the carcinoid group, the patients were 20 men and 4 women between the
ages of 25 and 78 years (mean, 48 years). These patients were symptomatic with
chest pain, shortness of breath, and dyspnea. One patient presented with
multiple endocrine neoplasia syndrome. Complete surgical resection was
accomplished in all patients. The 46 neuroendocrine tumors were evaluated for
GATA-3, pancytokeratin, thryoid transcription factor 1 (TTF-1), napsin A,
chromogranin A, and synaptophysin. All paragangliomas were universally positive
for chromogranin A and synaptophysin, but negative for pancytokeratin, TTF-1,
and napsin A. GATA-3 was expressed in 12 (55%) of 22 tumors. The thymic
neuroendocrine carcinomas (carcinoid tumors) were universally positive for
pancytokeratin, but negative for GATA-3 and napsin A. Chromogranin A and
synaptophysin were expressed in 92% and 88% of cases, respectively, and TTF-1 in
4 (17%) of 24 cases. Based on these results, we recommend that the workup of
neuroendocrine tumors should include not only the conventional neuroendocrine
markers and pancytokeratin but also other markers such as GATA-3 and TTF-1 in
order to arrive at a better interpretation.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.humpath.2014.08.013
PMID: 25294372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11486028 | 1. Mol Cell Biol. 2001 Sep;21(17):5889-98. doi: 10.1128/MCB.21.17.5889-5898.2001.
Loss of HuR is linked to reduced expression of proliferative genes during
replicative senescence.
Wang W(1), Yang X, Cristofalo VJ, Holbrook NJ, Gorospe M.
Author information:
(1)Laboratory of Cellular and Molecular Biology, National Institute on
Aging-Intramural Research Program, National Institutes of Health, 5600 Nathan
Shock Drive, Baltimore, MD 21224, USA.
Cellular aging is accompanied by alterations in gene expression patterns. Here,
using two models of replicative senescence, we describe the influence of the
RNA-binding protein HuR in regulating the expression of several genes whose
expression decreases during senescence. We demonstrate that HuR levels, HuR
binding to target mRNAs encoding proliferative genes, and the half-lives of such
mRNAs are lower in senescent cells. Importantly, overexpression of HuR in
senescent cells restored a "younger" phenotype, while a reduction in HuR
expression accentuated the senescent phenotype. Our studies highlight a critical
role for HuR during the process of replicative senescence.
DOI: 10.1128/MCB.21.17.5889-5898.2001
PMCID: PMC87308
PMID: 11486028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23833580 | 1. J Res Med Sci. 2012 Nov;17(11):1052-5.
Association of vitamin D deficiency and coronary artery disease with
cardiovascular risk factors.
Siadat ZD(1), Kiani K, Sadeghi M, Shariat AS, Farajzadegan Z, Kheirmand M.
Author information:
(1)Department of Community Medicine, Isfahan Cardiovascular Research Institute,
Isfahan University of Medical Sciences, Isfahan, Iran.
BACKGROUND: Vitamin D deficiency is a prevalent condition in many countries. The
aim of this study is to elucidate whether deficient vitamin D status is
associated with coronary artery disease considering cardiovascular risk factors.
MATERIALS AND METHODS: We measured 25 (OH) D serum levels in 57 patients that
were diagnosed with coronary artery disease upon coronary angiography and 62
individuals in the control group who were matched for age and sex with the
patients and examined the association between serum 25 (OH) D and coronary
artery disease with regard to cardiovascular risk factors.
RESULTS: The odds ratio of being affected by coronary artery disease in
individuals with vitamin D deficiency (25 (OH) D < 30 ng/ml) was 5.8 (1.77 -
18.94) after adjustment with cardiovascular risk factors, i.e., blood pressure,
diabetes, smoking, obesity, physical activity and high blood cholesterol in
comparison with the control group.
CONCLUSION: Low levels of 25 (OH) D are associated with prevalent coronary
artery disease independent of cardiovascular risk factors. Further
investigations could demonstrate the need for vitamin D supplementations in
order to prevent atherosclerosis.
PMCID: PMC3702087
PMID: 23833580
Conflict of interest statement: Conflict of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/9783696 | 1. J Med Virol. 1998 Nov;56(3):264-8.
Neutralization of HIV-1 subtypes: implications for vaccine formulations.
Smith TL(1), van Rensburg EJ, Engelbrecht S.
Author information:
(1)Department of Medical Virology, University of Stellenbosch and Tygerberg
Hospital, South Africa.
More than 20.8 million people are infected with HIV in sub-Saharan Africa, with
South Africa having one of the fastest growing HIV-1 epidemics, where an
estimated 2.4 million people were infected. Thirty-two sera from 25 patients
were tested for their ability to neutralize HTLV-IIIB (IIIB) and four primary
isolates representing subtypes B, C, D, and a recombinant gag C/env B type. A
CEM-SS cell line-based assay was used and the neutralizing titer was defined as
the reciprocal of the highest dilution giving a 50% reduction in p24 antigen
production. All isolates were neutralized better by subtype-specific sera,
except for the C4714 strain, which was neutralized by both subtype B and C sera.
C4714 was neutralized by 18/25 (72%) sera, IIIB by 19/32 (59%) sera, D482 by
7/31(23%) sera, B3245 by 6/29 (21%) sera, and the recombinant B/C1491 isolate by
4/25 (16%) sera. Five sera were unable to neutralize any of the isolates. The V3
region of the isolates used in the neutralization assay was amplified by PCR,
directly sequenced, and analyzed to reveal variability between the consensus
HIV-1 sequences and the isolates. HIV-1 strain C4714 was neutralized more
effectively with the sera tested than the IIIIB laboratory strain. Variability
in the amino acid sequence of the V3 region, which can alter the conformation of
the V3 loop secondary structure, can influence the neutralization of a
particular viral isolate. Vaccine formulations should be broadened to include
multiple subtypes, especially C subtypes, which is rapidly spreading worldwide.
PMID: 9783696 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19095434 | 1. Curr Opin Genet Dev. 2008 Dec;18(6):544-50. doi: 10.1016/j.gde.2008.11.001.
Epub 2008 Dec 16.
Rapidly evolving fish genomes and teleost diversity.
Ravi V(1), Venkatesh B.
Author information:
(1)Institute of Molecular and Cell Biology, Agency for Science, Technology and
Research, Biopolis, Singapore, Singapore.
Teleost fishes are the largest and most diverse group of vertebrates. The
diversity of teleosts has been attributed to a whole-genome duplication (WGD)
event in the ray-finned fish lineage. Recent comparative genomic studies have
revealed that teleost genomes have experienced frequent gene-linkage disruptions
compared to other vertebrates, and that protein-coding sequences in teleosts are
evolving faster than in mammals, irrespective of their duplication status. A
significant number of conserved noncoding elements (CNEs) shared between
cartilaginous fishes and tetrapods have diverged beyond recognition in teleost
fishes. The divergence of CNEs seems to have been initiated in basal ray-finned
fishes before the WGD. The fast evolving singleton and duplicated genes as well
as the divergent CNEs might have contributed to the diversity of teleost fishes.
DOI: 10.1016/j.gde.2008.11.001
PMID: 19095434 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17387144 | 1. Genome Res. 2007 May;17(5):545-55. doi: 10.1101/gr.6086307. Epub 2007 Mar 26.
Genomic regulatory blocks encompass multiple neighboring genes and maintain
conserved synteny in vertebrates.
Kikuta H(1), Laplante M, Navratilova P, Komisarczuk AZ, Engström PG, Fredman D,
Akalin A, Caccamo M, Sealy I, Howe K, Ghislain J, Pezeron G, Mourrain P,
Ellingsen S, Oates AC, Thisse C, Thisse B, Foucher I, Adolf B, Geling A, Lenhard
B, Becker TS.
Author information:
(1)Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen,
Norway.
We report evidence for a mechanism for the maintenance of long-range conserved
synteny across vertebrate genomes. We found the largest mammal-teleost conserved
chromosomal segments to be spanned by highly conserved noncoding elements
(HCNEs), their developmental regulatory target genes, and phylogenetically and
functionally unrelated "bystander" genes. Bystander genes are not specifically
under the control of the regulatory elements that drive the target genes and are
expressed in patterns that are different from those of the target genes.
Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2,
rx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the
expression patterns of these genes even if located inside or beyond bystander
genes, suggesting that the regulatory domain of a developmental regulatory gene
can extend into and beyond adjacent transcriptional units. We termed these
chromosomal segments genomic regulatory blocks (GRBs). After whole genome
duplication in teleosts, GRBs, including HCNEs and target genes, were often
maintained in both copies, while bystander genes were typically lost from one
GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy
GRBs of higher vertebrates intact. We show that loss of bystander genes and
other mutational events suffered by duplicated GRBs in teleost genomes permits
target gene identification and HCNE/target gene assignment. These findings
explain the absence of evolutionary breakpoints from large vertebrate
chromosomal segments and will aid in the recognition of position effect
mutations within human GRBs.
DOI: 10.1101/gr.6086307
PMCID: PMC1855176
PMID: 17387144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16877549 | 1. Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2597-605. doi:
10.1152/ajpheart.00393.2006. Epub 2006 Jul 28.
Electrophysiological mechanisms of ventricular arrhythmias in relation to
Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study.
Sung RJ(1), Wu SN, Wu JS, Chang HD, Luo CH.
Author information:
(1)Dept. of Medicine, College of Medicine, National Cheng Kung University,
Tainan, Taiwan 704. [email protected]
Patients with Andersen-Tawil syndrome (ATS) mostly have mutations on the KCNJ2
gene, producing loss of function or dominant-negative suppression of the inward
rectifier K(+) channel Kir2.1. However, clinical manifestations of ATS including
dysmorphic features, periodic paralysis (hypo-, hyper-, or normokalemic), long
QT, and ventricular arrhythmias (VAs) are considerably variable. Using a
modified dynamic Luo-Rudy simulation model of cardiac ventricular myocytes, we
attempted to elucidate mechanisms of VA in ATS by analyzing effects of the
inward rectifier K(+) channel current (I(K1)) on the action potential (AP).
During pacing at 1.0 Hz with extracellular K(+) concentration ([K(+)](o)) at 4.5
mM, a stepwise 10% reduction of Kir2.1 channel conductance progressively
prolonged the terminal repolarization phase of the AP along with gradual
depolarization of the resting membrane potential (RMP). At 90% reduction, early
afterdepolarizations (EADs) became inducible and RMP was depolarized to -52.0 mV
(control: -89.8 mV), followed by emergence of spontaneous APs. Both EADs and
spontaneous APs were facilitated by a decrease in [K(+)](o) and suppressed by an
increase in [K(+)](o). Simulated beta-adrenergic stimulation enhanced delayed
afterdepolarizations (DADs) and could also facilitate EADs as well as
spontaneous APs in the setting of low [K(+)](o) and reduced Kir2.1 channel
conductance. In conclusion, the spectrum of VAs in ATS may include 1) triggered
activity mediated by EADs and/or DADs and 2) abnormal automaticity manifested as
spontaneous APs. These VAs can be aggravated by a decrease in [K(+)](o) and
beta-adrenergic stimulation and may potentially induce torsade de pointes and
cause sudden death. In patients with ATS, the hypokalemic form of periodic
paralysis should have the highest propensity to VAs, especially during physical
activity.
DOI: 10.1152/ajpheart.00393.2006
PMID: 16877549 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8374893 | 1. Cancer Genet Cytogenet. 1993 Aug;69(1):13-6. doi:
10.1016/0165-4608(93)90104-t.
Fanconi anemia. Chromosome breakage and cell cycle studies.
Berger R(1), Le Coniat M, Gendron MC.
Author information:
(1)INSERM U 301, Institut de Génétique Moléculaire, Paris, France.
The experience with cytogenetic and flow cytometry methods used for the
diagnosis of Fanconi anemia (FA) in one center is summarized. The tests consist
of chromosomal breakage and cell cycle studied after sensitization by the
introduction of nitrogen mustard into phytohemagglutinin-stimulated blood-cell
cultures. The cytogenetic test was shown to be reliable in ascertaining the
diagnosis of FA. Flow cytometry studies showed a marked increase in the
percentage of cells in G2/M phase in FA patients after sensitization by nitrogen
mustard. This increase, however, could not be detected in three FA patients with
myelodysplasia or acute leukemia and the results were ambiguous on three
occasions.
DOI: 10.1016/0165-4608(93)90104-t
PMID: 8374893 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22781932 | 1. Reprod Fertil Dev. 2012;24(6):813-21. doi: 10.1071/RD11205.
IVMBIX-01294, an inhibitor of the histone methyltransferase EHMT2, disrupts
histone H3 lysine 9 (H3K9) dimethylation in the cleavage-stage porcine embryo.
Park KE(1), Johnson CM, Cabot RA.
Author information:
(1)Department of Animal Sciences, Purdue University, 915 West State Street, West
Lafayette, IN 47907, USA.
Global patterns of histone methylation are remodelled during cleavage
development. Of the five histone methyltransferases known to mediate methylation
of the lysine 9 residue of histone H3 (H3K9), euchromatic histone-lysine
N-methyltransferase 2 (EHMT2; also known as G9a) has been shown to be a primary
mediator of H3K9 dimethylation; BIX-01294 has been shown to be a specific
inhibitor of EHMT2. The objective of the present study was to determine the
effect of BIX-01294 treatment on global H3K9 dimethylation in porcine embryos.
We hypothesised that inhibition of EHMT2 by BIX-01294 would result in reduced
levels of H3K9 dimethylation and compromised embryo development. Our results
showed that incubation in 5µM BIX-01294 markedly reduced global levels of H3K9
dimethylation at the pronuclear, 2-cell and 4-cell stages of development and
resulted in developmental arrest before blastocyst formation. Although transient
exposure of embryos to BIX-01294 did not alter in vitro development, embryos
transiently exposed to BIX-01294 did not establish pregnancy. These data
demonstrate that BIX-01294 is a potent inhibitor of H3K9 dimethylation and that
transient alterations in global histone modifications can have profound effects
on embryo developmental potential.
DOI: 10.1071/RD11205
PMID: 22781932 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21919874 | 1. Curr Pharm Des. 2011 Oct;17(30):3280-94. doi: 10.2174/138161211797904190.
Stem cells in cardiovascular regeneration: from preservation of endogenous
repair to future cardiovascular therapies.
Templin C(1), Kränkel N, Lüscher TF, Landmesser U.
Author information:
(1)Cardiovascular Center, University Hospital Zurich, CH-8091 Zürich,
Switzerland.
Cardiovascular disease remains the leading cause of morbidity and mortality in
the developed countries. This review summarizes current pre-clinical and
clinical evidence for the potential role and mechanisms of action of stem and
progenitor cells in vascular and cardiac repair and regeneration. Apart from
cell transplantation strategies, approaches to maintain stem cell niche function
and targeting mobilization/recruitment of specific stem/progenitor cell
populations may aid in preserving vascular and cardiac function. Moreover, with
the use of patient-derived induced pluripotent stem cells, the field of
regenerative medicine is entering a new era. Potential applications of induced
pluripotent stem cells and direct reprogrammed cells as well as recent
developments in tissue engineering are discussed.
DOI: 10.2174/138161211797904190
PMID: 21919874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23945944 | 1. Nucleic Acids Res. 2013 Oct;41(19):e180. doi: 10.1093/nar/gkt721. Epub 2013
Aug 13.
Baculoviral transduction facilitates TALEN-mediated targeted transgene
integration and Cre/LoxP cassette exchange in human-induced pluripotent stem
cells.
Zhu H(1), Lau CH, Goh SL, Liang Q, Chen C, Du S, Phang RZ, Tay FC, Tan WK, Li Z,
Tay JC, Fan W, Wang S.
Author information:
(1)Department of Biological Sciences, National University of Singapore, 117543
Singapore, Department of Surgery, Program of Innovative Cancer Therapeutics,
First Affiliated Hospital of Zhejiang University College of Medicine, 310009
Hangzhou, China and Institute of Bioengineering and Nanotechnology, 138669
Singapore.
Safety and reliability of transgene integration in human genome continue to pose
challenges for stem cell-based gene therapy. Here, we report a
baculovirus-transcription activator-like effector nuclease system for AAVS1
locus-directed homologous recombination in human induced pluripotent stem cells
(iPSCs). This viral system, when optimized in human U87 cells, provided a
targeted integration efficiency of 95.21% in incorporating a Neo-eGFP cassette
and was able to mediate integration of DNA insert up to 13.5 kb. In iPSCs,
targeted integration with persistent transgene expression was achieved without
compromising genomic stability. The modified iPSCs continued to express stem
cell pluripotency markers and maintained the ability to differentiate into three
germ lineages in derived embryoid bodies. Using a baculovirus-Cre/LoxP system in
the iPSCs, the Neo-eGFP cassette at the AAVS1 locus could be replaced by a
Hygro-mCherry cassette, demonstrating the feasibility of cassette exchange.
Moreover, as assessed by measuring γ-H2AX expression levels, genome toxicity
associated with chromosomal double-strand breaks was not detectable after
transduction with moderate doses of baculoviral vectors expressing transcription
activator-like effector nucleases. Given high targeted integration efficiency,
flexibility in transgene exchange and low genome toxicity, our baculoviral
transduction-based approach offers great potential and attractive option for
precise genetic manipulation in human pluripotent stem cells.
DOI: 10.1093/nar/gkt721
PMCID: PMC3799456
PMID: 23945944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23264734 | 1. J Cell Sci. 2013 Feb 1;126(Pt 3):722-31. doi: 10.1242/jcs.112375. Epub 2012
Dec 21.
Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell
adhesion and migration.
Allaire PD(1), Seyed Sadr M, Chaineau M, Seyed Sadr E, Konefal S, Fotouhi M,
Maret D, Ritter B, Del Maestro RF, McPherson PS.
Author information:
(1)Department of Neurology and Neurosurgery, Montreal Neurological Institute,
McGill University, Montreal, QC H3A 2B4, Canada.
Cells inversely adjust the plasma membrane levels of integrins and cadherins
during cell migration and cell-cell adhesion but the regulatory mechanisms that
coordinate these trafficking events remain unknown. Here, we demonstrate that
the small GTPase Rab35 maintains cadherins at the cell surface to promote
cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase
Arf6 to downregulate an Arf6-dependent recycling pathway for β1-integrin and EGF
receptors, resulting in inhibition of cell migration and attenuation of
signaling downstream of these receptors. Importantly, the phenotypes of
decreased cell adhesion and increased cell migration observed following Rab35
knock down are consistent with the epithelial-mesenchymal transition, a feature
of invasive cancer cells, and we show that Rab35 expression is suppressed in a
subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a
key molecular mechanism that efficiently coordinates the inverse intracellular
sorting and cell surface levels of cadherin and integrin receptors for cell
migration and differentiation.
DOI: 10.1242/jcs.112375
PMID: 23264734 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10439043 | 1. Oncogene. 1999 Jul 29;18(30):4357-63. doi: 10.1038/sj.onc.1202825.
Inhibition of mammalian cell proliferation by genetically selected peptide
aptamers that functionally antagonize E2F activity.
Fabbrizio E(1), Le Cam L, Polanowska J, Kaczorek M, Lamb N, Brent R, Sardet C.
Author information:
(1)Institut de Génétique Moléculaire, UMR 5535 CNRS, Montpellier, France.
The p16-cyclin D-pRB-E2F pathway is frequently deregulated in human tumors. This
critical regulatory pathway controls the G1/S transition of the mammalian cell
cycle by positive and negative regulation of E2F-responsive genes required for
DNA replication. To assess the value of the transcription factors E2Fs as
targets for antiproliferative strategies, we have initiated a program aiming to
develop inhibitors targeting specifically these proteins in vitro and in vivo.
The cellular activity of E2F is the result of the heterodimeric association of
two families of proteins, E2Fs and DPs, which then bind DNA. Here, we use a two
hybrid approach to isolate from combinatorial libraries peptide aptamers that
specifically interact with E2Fs DNA binding and dimerization domains. One of
these is a potent inhibitor of E2F binding activity in vitro and in mammalian
fibroblasts, blocks cells in G1, and the free variable region from this aptamer
has the same effect. Our experiments argue that the variable region of this
aptamer is structured, and that it functions by binding E2F with a motif that
resembles a DP heterodimerization region, and blocking E2F's association with
DP. These results show that cell proliferation can be inhibited using
genetically-selected synthetic peptides that specifically target protein-protein
interaction motifs within cell cycle regulators. These results also emphasize
the critical role of the E2F pathway for cell proliferation and might allow the
design of novel antiproliferative agents targeting the cyclin/CDK-pRB-E2F
pathway.
DOI: 10.1038/sj.onc.1202825
PMID: 10439043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24143074 | 1. Biologics. 2013;7:211-21. doi: 10.2147/BTT.S25095. Epub 2013 Oct 10.
Everolimus in the treatment of subependymal giant cell astrocytomas,
angiomyolipomas, and pulmonary and skin lesions associated with tuberous
sclerosis complex.
Franz DN(1).
Author information:
(1)Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's
Hospital Medical Center, Cincinnati, OH, USA.
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder
caused by inactivating mutations in either the TSC1 or TSC2 genes. It is
characterized by the development of multiple, benign tumors in several organs
throughout the body. Lesions occur in the brain, kidneys, heart, liver, lungs,
and skin and result in seizures and epilepsy, mental retardation, autism, and
renal and pulmonary organ system dysfunction, as well as other complications.
Elucidation of the molecular pathways and etiological factors responsible for
causing TSC has led to a paradigm shift in the management and treatment of the
disease. TSC1 or TSC2 mutations lead to constitutive upregulation of the
mammalian target of rapamycin pathway, which affects many cellular processes
involved in tumor growth. By targeting mammalian target of rapamycin with
everolimus, an orally active rapamycin derivative, clinically meaningful and
statistically significant reductions in tumor burden have been achieved for the
main brain (subependymal giant cell astrocytoma) and renal manifestations
(angiomyolipoma) associated with TSC. This review provides an overview of TSC,
everolimus, and the clinical trials that led to its approval for the treatment
of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma.
DOI: 10.2147/BTT.S25095
PMCID: PMC3797614
PMID: 24143074 |
http://www.ncbi.nlm.nih.gov/pubmed/22454518 | 1. J Cell Sci. 2012 Jul 1;125(Pt 13):3195-201. doi: 10.1242/jcs.101683. Epub 2012
Mar 27.
Phosphoinositide specificity determines which cytohesins regulate β1 integrin
recycling.
Oh SJ(1), Santy LC.
Author information:
(1)Department of Biochemistry and Molecular Biology, Pennsylvania State
University, University Park, PA 16802, USA.
Recycling of internalized integrins is a crucial step in adhesion remodeling and
cell movement. Recently, we determined that the ADP-ribosylation factor-guanine
nucleotide exchange factors (ARF-GEFs) cytohesin 2/ARNO and cytohesin 3/GRP1
have opposing effects on adhesion and stimulated β1 integrin recycling even
though they are very closely related proteins (80% sequence identity). We have
now determined the sequence differences underlying the differential actions of
cytohesin 2/ARNO and cytohesin 3/GRP1. We found that the ability of cytohesins
to promote β1 integrin recycling and adhesion depends upon the presence or
absence of a key glycine residue in their pleckstrin homology (PH) domains. This
glycine residue determines the phosphoinositide specificity and affinity of
cytohesin PH domains. Switching the number of glycines in the PH domains of
cytohesin 2 and cytohesin 3 is sufficient to reverse their effects on adhesion
and spreading and to reverse their subcellular locations. Importantly, we also
find that a mutant form of cytohesin 3/GRP1 that has three rather than two
glycines in its PH domain rescues β1 integrin recycling in cytohesin 2/ARNO
knockdown cells. Conversely, a mutant form of cytohesin 2/ARNO with two glycines
in its PH domain fails to rescue β1 integrin recycling. Therefore, we conclude
that phosphoinositide specificity is the sole functional difference that
determines which cytohesin can promote integrin recycling.
DOI: 10.1242/jcs.101683
PMID: 22454518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22718819 | 1. J Virol. 2012 Sep;86(17):8949-58. doi: 10.1128/JVI.01053-12. Epub 2012 Jun 20.
Large ribosomal protein 4 increases efficiency of viral recoding sequences.
Green L(1), Houck-Loomis B, Yueh A, Goff SP.
Author information:
(1)Department of Biological Sciences, College of Physicians and Surgeons,
Columbia University, New York, New York, USA.
Expression of retroviral replication enzymes (Pol) requires a controlled
translational recoding event to bypass the stop codon at the end of gag. This
recoding event occurs either by direct suppression of termination via the
insertion of an amino acid at the stop codon (readthrough) or by alteration of
the mRNA reading frame (frameshift). Here we report the effects of a host
protein, large ribosomal protein 4 (RPL4), on the efficiency of recoding. Using
a dual luciferase reporter assay, we found that transfection of cells with a
plasmid encoding RPL4 cDNA increases recoding efficiency in a dose-dependent
manner, with a maximal enhancement of nearly twofold. Expression of RPL4
increases recoding of reporters containing retroviral readthrough and frameshift
sequences, as well as the Sindbis virus leaky termination signal. RPL4-induced
enhancement of recoding is cell line specific and appears to be specific to RPL4
among ribosomal proteins. Cotransfection of RPL4 cDNA with Moloney murine
leukemia proviral DNA results in Gag processing defects and a reduction of viral
particle formation, presumably caused by the RPL4-dependent alteration of the
Gag-to-Gag-Pol ratio required for virion assembly and release.
DOI: 10.1128/JVI.01053-12
PMCID: PMC3416150
PMID: 22718819 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24518170 | 1. J Pediatr. 2014 May;164(5):1195-200. doi: 10.1016/j.jpeds.2013.12.053. Epub
2014 Feb 8.
Mammalian target of rapamycin inhibitors for intractable epilepsy and
subependymal giant cell astrocytomas in tuberous sclerosis complex.
Cardamone M(1), Flanagan D(2), Mowat D(3), Kennedy SE(4), Chopra M(5), Lawson
JA(2).
Author information:
(1)Department of Neurology, Sydney Children's Hospital, Randwick, New South
Wales, Australia; The School of Women's and Children's Health, Medicine UNSW,
University of New South Wales, Sydney, New South Wales, Australia. Electronic
address: [email protected].
(2)Department of Neurology, Sydney Children's Hospital, Randwick, New South
Wales, Australia; The School of Women's and Children's Health, Medicine UNSW,
University of New South Wales, Sydney, New South Wales, Australia.
(3)Department of Medical Genetics, Sydney Children's Hospital, Randwick, New
South Wales, Australia; The School of Women's and Children's Health, Medicine
UNSW, University of New South Wales, Sydney, New South Wales, Australia.
(4)Department of Nephrology, Sydney Children's Hospital, Randwick, New South
Wales, Australia; The School of Women's and Children's Health, Medicine UNSW,
University of New South Wales, Sydney, New South Wales, Australia.
(5)Department of Medical Genetics, Sydney Children's Hospital, Randwick, New
South Wales, Australia.
OBJECTIVES: To evaluate the efficacy and side effects of oral mammalian target
of rapamycin (mTOR) inhibitors in children and adolescents with tuberous
sclerosis complex (TSC) and intractable epilepsy or subependymal giant cell
astrocytoma (SEGA).
STUDY DESIGN: Single-center series of 13 children and adolescents with TSC who
received sirolimus or everolimus (mTOR inhibitors). The anticonvulsant response
was evaluated in 7 patients with TSC and refractory seizures. Six patients with
SEGAs were treated with either sirolimus or everolimus for nonsurgical
management. SEGA volumes were assessed longitudinally using 1.5-T magnetic
resonance imaging.
RESULTS: Of the intractable seizure group (7 patients), 1 patient had >90%
reduction, 4 had 50%-90% reduction, and 2 had <50% reduction. Three reported
subjective improvements in learning. By 12 months of treatment, there were
statistically significant reductions in the SEGA volumes in 4 patients who
received mTOR inhibitors (P < .04). The mean SEGA volume after 6 months of
treatment was 2.18 cm(3), which represents 33% reduction in the mean baseline
volume of 3.26 cm(3). The mTOR inhibitors were well tolerated. Adverse effects
include dyslipidaemia (3 of 13), gingivitis (1 of 13), anorexia (1 of 13), and
mild gastrointestinal side effects (1 of 13).
CONCLUSION: This case series suggests that mTOR inhibitors can improve seizures
in those with TSC and refractory epilepsy. They are also an effective treatment
for reducing the volume of SEGAs in patients with TSC not amenable to surgery
with an acceptable side effect profile.
Crown Copyright © 2014. Published by Mosby, Inc. All rights reserved.
DOI: 10.1016/j.jpeds.2013.12.053
PMID: 24518170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23738993 | 1. Compend Contin Educ Dent. 2011 Sep;32(7):E110-4.
Direct restorative treatment of dental erosion caused by gastroesophageal reflux
disease associated with bruxism: a case report.
Vidal Cde M(1), Catelan A, Briso AL, dos Santos PH.
Author information:
(1)Department of Restorative Dentistry, Araçatuba School of Dentistry-UNESP, São
Paulo, Brazil.
Gastroesophageal reflux disease (GERD) is a gastrointestinal disorder in which
stomach acids are chronically regurgitated into the esophagus and oral cavity.
Continual exposure of the teeth to these acids can cause severe tooth wear.
Dentists are often the first healthcare professionals to diagnose dental erosion
in patients with GERD. This article presents a case report of a 27-year-old male
smoker with tooth wear and dentin sensitivity caused by GERD associated with
bruxism. After diagnosis, a multidisciplinary treatment plan was established.
The initial treatment approach consisted of medical follow-up with counseling on
dietary and smoking habits, as well as management of the gastric disorders with
medication. GERD management and the dental treatment performed for the eroded
dentition are described, including diagnosis, treatment planning, and
restorative therapy.
PMID: 23738993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18832581 | 1. Am J Pathol. 2008 Nov;173(5):1275-85. doi: 10.2353/ajpath.2008.080365. Epub
2008 Oct 2.
Transforming growth factor-beta regulates in vitro heart valve repair by
activated valve interstitial cells.
Liu AC(1), Gotlieb AI.
Author information:
(1)Department of Laboratory Medicine and Pathobiology, University of Toronto,
Ontario, Canada.
The regulation of valve interstitial cell (VIC) function in response to tissue
injury and valve disease is not well understood. Because transforming growth
factor-beta (TGF-beta) has been implicated in tissue repair, we tested the
hypothesis that TGF-beta is a regulator of VIC activation and associated cell
responses that occur during early repair processes. We used a well-characterized
wound model that was created by mechanical denudation of a confluent VIC
monolayer to study activation and repair 24 hours after wounding. VIC activation
was demonstrated by immunofluorescent localization of alpha-smooth muscle actin
(alpha-SMA), and alpha-SMA mRNA levels were quantified by real-time polymerase
chain reaction. Proliferation and apoptosis were quantified by bromodeoxyuridine
staining and terminal deoxynucleotidyl transferase dUTP nick end labeling,
respectively. Repair was quantified by measuring VIC extension into the wound,
and TGF-beta expression was shown by immunofluorescent localization of
intracellular TGF-beta. Compared with nonwounded monolayers, VICs at the wound
edge showed alpha-SMA staining, increased alpha-SMA mRNA content, elongation
into the wound with stress fibers, proliferation, and apoptosis. VICs at the
wound edge also showed increased TGF-beta and pSmad2/3 staining with
co-expression of alpha-SMA. Addition of TGF-beta neutralizing antibody to the
wound decreased VIC activation, alpha-SMA mRNA content, proliferation,
apoptosis, wound closure rate, and stress fibers. Conversely, exogenous addition
of TGF-beta to the wound increased VIC activation, proliferation, wound closure
rate, and stress fibers. Thus, wounding activates VICs, and TGF-beta signaling
modulates VIC response to injury.
DOI: 10.2353/ajpath.2008.080365
PMCID: PMC2570119
PMID: 18832581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23393190 | 1. Nucleic Acids Res. 2013 Apr 1;41(6):3600-18. doi: 10.1093/nar/gkt030. Epub
2013 Feb 7.
Highly conserved elements discovered in vertebrates are present in non-syntenic
loci of tunicates, act as enhancers and can be transcribed during development.
Sanges R(1), Hadzhiev Y, Gueroult-Bellone M, Roure A, Ferg M, Meola N, Amore G,
Basu S, Brown ER, De Simone M, Petrera F, Licastro D, Strähle U, Banfi S,
Lemaire P, Birney E, Müller F, Stupka E.
Author information:
(1)Laboratory of Animal Physiology and Evolution, Stazione Zoologica Anton
Dohrn, Villa Comunale, 80121 Naples, Italy.
Co-option of cis-regulatory modules has been suggested as a mechanism for the
evolution of expression sites during development. However, the extent and
mechanisms involved in mobilization of cis-regulatory modules remains elusive.
To trace the history of non-coding elements, which may represent candidate
ancestral cis-regulatory modules affirmed during chordate evolution, we have
searched for conserved elements in tunicate and vertebrate (Olfactores) genomes.
We identified, for the first time, 183 non-coding sequences that are highly
conserved between the two groups. Our results show that all but one element are
conserved in non-syntenic regions between vertebrate and tunicate genomes, while
being syntenic among vertebrates. Nevertheless, in all the groups, they are
significantly associated with transcription factors showing specific functions
fundamental to animal development, such as multicellular organism development
and sequence-specific DNA binding. The majority of these regions map onto
ultraconserved elements and we demonstrate that they can act as functional
enhancers within the organism of origin, as well as in cross-transgenesis
experiments, and that they are transcribed in extant species of Olfactores. We
refer to the elements as 'Olfactores conserved non-coding elements'.
DOI: 10.1093/nar/gkt030
PMCID: PMC3616699
PMID: 23393190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10590441 | 1. Prenat Diagn. 1999 Dec;19(12):1177. doi:
10.1002/(sici)1097-0223(199912)19:12<1177::aid-pd713>3.0.co;2-q.
Risk of cystic fibrosis with prenatally detected echogenic bowel.
Ferriman EL, Mason G, Ellis L.
Comment on
Prenat Diagn. 1999 Jul;19(7):604-9.
DOI: 10.1002/(sici)1097-0223(199912)19:12<1177::aid-pd713>3.0.co;2-q
PMID: 10590441 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20582973 | 1. Pediatr Blood Cancer. 2010 Aug;55(2):314-7. doi: 10.1002/pbc.22537.
Cyclic neutropenia and severe congenital neutropenia in patients with a shared
ELANE mutation and paternal haplotype: evidence for phenotype determination by
modifying genes.
Newburger PE(1), Pindyck TN, Zhu Z, Bolyard AA, Aprikyan AA, Dale DC, Smith GD,
Boxer LA.
Author information:
(1)Department of Pediatrics, University of Massachusetts Medical School,
Worcester, Massachusetts 01655, USA. [email protected]
BACKGROUND: Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are
disorders of neutrophil production that differ markedly in disease severity.
Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered
largely responsible for most cases of CN and SCN, but specific mutations are
typically associated with one or the other.
PROCEDURE: We performed ELANE genotyping on all individuals and paternal sperm
in an SCN kindred with eight SCN progeny of a sperm donor and six different
mothers.
RESULTS: One patient with CN had the same S97L ELANE mutation as seven patients
with the SCN phenotype. The mutant allele was detected in the donor's
spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his
lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism.
CONCLUSIONS: The coexistence of CN and SCN phenotypes in this kindred with a
shared paternal haplotype strongly suggests both a role for modifying genes in
determination of congenital neutropenia disease phenotypes, and the
classification of CN and SCN within a spectrum of phenotypes expressing varying
degrees of the same disease process.
(c) 2010 Wiley-Liss, Inc.
DOI: 10.1002/pbc.22537
PMCID: PMC2913300
PMID: 20582973 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST STATEMENT None |
http://www.ncbi.nlm.nih.gov/pubmed/22765842 | 1. Stem Cells Dev. 2012 Nov 20;21(17):3081-90. doi: 10.1089/scd.2012.0277. Epub
2012 Aug 7.
TGFβ-dependent epithelial-to-mesenchymal transition is required to generate
cardiospheres from human adult heart biopsies.
Forte E(1), Miraldi F, Chimenti I, Angelini F, Zeuner A, Giacomello A, Mercola
M, Messina E.
Author information:
(1)Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti
Foundation, Sapienza University of Rome, Rome, Italy.
Autologous cardiac progenitor cells (CPCs) isolated as cardiospheres (CSps)
represent a promising candidate for cardiac regenerative therapy. A better
understanding of the origin and mechanisms underlying human CSps formation and
maturation is undoubtedly required to enhance their cardiomyogenic potential.
Epithelial-to-mesenchymal transition (EMT) is a key morphogenetic process that
is implicated in the acquisition of stem cell-like properties in different adult
tissues, and it is activated in the epicardium after ischemic injury to the
heart. We investigated whether EMT is involved in the formation and
differentiation of human CSps, revealing that an up-regulation of the expression
of EMT-related genes accompanies CSps formation that is relative to primary
explant-derived cells and CSp-derived cells grown in a monolayer. EMT and CSps
formation is enhanced in the presence of transforming growth factor β1 (TGFβ1)
and drastically blocked by the type I TGFβ-receptor inhibitor SB431452,
indicating that TGFβ-dependent EMT is essential for the formation of these
niche-like 3D-multicellular clusters. Since TGFβ is activated in the myocardium
in response to injury, our data suggest that CSps formation mimics an adaptive
mechanism that could potentially be enhanced to increase in vivo or ex vivo
regenerative potential of adult CPCs.
DOI: 10.1089/scd.2012.0277
PMCID: PMC4146498
PMID: 22765842 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11001877 | 1. Blood. 2000 Oct 1;96(7):2317-22.
Mutations in the gene encoding neutrophil elastase in congenital and cyclic
neutropenia.
Dale DC(1), Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, Boxer LA,
Kannourakis G, Zeidler C, Welte K, Benson KF, Horwitz M.
Author information:
(1)Divisions of Hematology and Medical Genetics, Department of Medicine and the
Markey Molecular Medicine Center, University of Washington School of Medicine,
Seattle, WA, USA. [email protected]
Comment in
Blood. 2001 Apr 1;97(7):2185-6. doi: 10.1182/blood.v97.7.2185.
Congenital neutropenia and cyclic neutropenia are disorders of neutrophil
production predisposing patients to recurrent bacterial infections. Recently the
locus for autosomal dominant cyclic neutropenia was mapped to chromosome
19p13.3, and this disease is now attributable to mutations of the gene encoding
neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital
neutropenia is also due to mutations of neutrophil elastase. Patients with
congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were
referred to the Severe Chronic Neutropenia International Registry. Referring
physicians provided hematologic and clinical data. Mutational analysis was
performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA
for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking
regions. RNA from bone marrow mononuclear cells was used to determine if the
affected patients expressed both the normal and the abnormal transcript.
Twenty-two of 25 patients with congenital neutropenia had 18 different
heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3
patients with Shwachman-Diamond syndrome had mutations. For 5 patients with
congenital neutropenia having mutations predicted to alter RNA splicing or
transcript structure, reverse transcriptase-PCR showed expression of both normal
and abnormal transcripts. In cyclic neutropenia, the mutations appeared to
cluster near the active site of the molecule, whereas the opposite face was
predominantly affected by the mutations found in congenital neutropenia. This
study indicates that mutations of the gene encoding neutrophil elastase are
probably the most common cause for severe congenital neutropenia as well as the
cause for sporadic and autosomal dominant cyclic neutropenia.
PMID: 11001877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19678847 | 1. FEMS Yeast Res. 2009 Dec;9(8):1137-47. doi: 10.1111/j.1567-1364.2009.00552.x.
Epub 2009 Jul 16.
Calcium homeostasis and signaling in yeast cells and cardiac myocytes.
Cui J(1), Kaandorp JA, Sloot PM, Lloyd CM, Filatov MV.
Author information:
(1)Department of Computer Science, National University of Singapore, Singapore,
Singapore. [email protected]
Calcium ions are the most ubiquitous and versatile signaling molecules in
eukaryotic cells. Calcium homeostasis and signaling systems are crucial for both
the normal growth of the budding yeast Saccharomyces cerevisiae and the
intricate working of the mammalian heart. In this paper, we make a detailed
comparison between the calcium homeostasis/signaling networks in yeast cells and
those in mammalian cardiac myocytes. This comparison covers not only the
components, structure and function of the networks but also includes existing
knowledge on the measured and simulated network dynamics using mathematical
models. Surprisingly, most of the factors known in the yeast calcium
homeostasis/signaling network are conserved and operate similarly in mammalian
cells, including cardiac myocytes. Moreover, the budding yeast S. cerevisiae is
a simple organism that affords powerful genetic and genomic tools. Thus,
exploring and understanding the calcium homeostasis/signaling system in yeast
can provide a shortcut to help understand calcium homeostasis/signaling systems
in mammalian cardiac myocytes. In turn, this knowledge can be used to help treat
relevant human diseases such as pathological cardiac hypertrophy and heart
failure.
DOI: 10.1111/j.1567-1364.2009.00552.x
PMID: 19678847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18279518 | 1. Genome Biol. 2008;9(2):R34. doi: 10.1186/gb-2008-9-2-r34. Epub 2008 Feb 15.
Ancora: a web resource for exploring highly conserved noncoding elements and
their association with developmental regulatory genes.
Engström PG(1), Fredman D, Lenhard B.
Author information:
(1)Computational Biology Unit, Bergen Center for Computational Science,
University of Bergen, Thormøhlensgate, N-5008 Bergen, Norway.
[email protected]
Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs)
that span developmental regulatory genes and define regulatory domains. We
describe Ancora http://ancora.genereg.net, a web resource that provides data and
tools for exploring genomic organization of HCNEs for multiple genomes. Ancora
includes a genome browser that shows HCNE locations and features novel HCNE
density plots as a powerful tool to discover developmental regulatory genes and
distinguish their regulatory elements and domains.
DOI: 10.1186/gb-2008-9-2-r34
PMCID: PMC2374709
PMID: 18279518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21611174 | 1. PLoS One. 2011;6(5):e19809. doi: 10.1371/journal.pone.0019809. Epub 2011 May
18.
Wnt3a induces myofibroblast differentiation by upregulating TGF-β signaling
through SMAD2 in a β-catenin-dependent manner.
Carthy JM(1), Garmaroudi FS, Luo Z, McManus BM.
Author information:
(1)UBC James Hogg Research Centre, Institute for Heart+Lung Health, Department
of Pathology and Laboratory Medicine, University of British Columbia, Vancouver,
British Columbia, Canada.
Growing evidence suggests the Wnt family of secreted glycoproteins and their
associated signaling pathways, linked to development, are recapitulated during
wound repair and regeneration events. However, the role of the Wnt pathway in
such settings remains unclear. In the current study, we treated mouse
fibroblasts with 250 ng/mL of recombinant Wnt3a for 72 hours and examined its
affect on cell morphology and function. Wnt3a induced a spindle-like morphology
in fibroblasts characterized by the increased formation of stress fibres. Wnt3a
decreased the proliferation of fibroblasts, but significantly increased cell
migration as well as fibroblast-mediated contraction of a collagen lattice.
Wnt3a significantly increased the expression of TGF-β and its associated
signaling through SMAD2. Consistent with this, we observed significantly
increased smooth muscle α-actin expression and incorporation of this contractile
protein into stress fibres following Wnt3a treatment. Knockdown of β-catenin
using siRNA reversed the Wnt3a-induced smooth muscle α-actin expression,
suggesting these changes were dependent on canonical Wnt signaling through
β-catenin. Neutralization of TGF-β with a blocking antibody significantly
inhibited the Wnt3a-induced smooth muscle α-actin expression, indicating these
changes were dependent on the increased TGF-β signaling. Collectively, this data
strongly suggests Wnt3a promotes the formation of a myofibroblast-like phenotype
in cultured fibroblasts, in part, by upregulating TGF-β signaling through SMAD2
in a β-catenin-dependent mechanism. As myofibroblasts are critical regulators of
wound healing responses, these findings may have important implications for our
understanding of normal and aberrant injury and repair events.
DOI: 10.1371/journal.pone.0019809
PMCID: PMC3097192
PMID: 21611174 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/23686401 | 1. Support Care Cancer. 2013 Aug;21(8):2341-9. doi: 10.1007/s00520-013-1826-3.
Epub 2013 May 19.
Management of adverse events in patients with hormone receptor-positive breast
cancer treated with everolimus: observations from a phase III clinical trial.
Peterson ME(1).
Author information:
(1)Banner MD Anderson Cancer Center, 2940 Banner Gateway Drive, Suite 400,
Gilbert, AZ 85234, USA. [email protected]
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the
treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors,
subependymal giant cell astrocytoma associated with tuberous sclerosis complex,
renal angiomyolipoma and tuberous sclerosis complex, and, in combination with
exemestane, for hormone receptor-positive HER2-negative advanced breast cancer
after failure of treatment with letrozole or anastrozole. Results from the phase
III BOLERO-2 trial demonstrated that everolimus in combination with exemestane
provided significant clinical benefit to patients with advanced hormone
receptor-positive breast cancer. Although everolimus is generally well
tolerated, as with most therapies administered in an advanced cancer setting,
drug-related adverse events (AEs) inevitably occur. Most common AEs observed in
the everolimus studies include stomatitis, rash, infection, noninfectious
pneumonitis, and hyperglycemia. Clinical awareness and early identification of
such AEs by oncology nurses are essential to dosing (interruptions, reduction,
and treatment discontinuation); quality of life; and, ultimately, patient
outcomes. Because everolimus has already been shown to significantly improve
clinical efficacy in patients with advanced breast cancer, a proactive approach
to the practical management of AEs associated with this mTOR inhibitor as well
as other most common AEs observed in this patient population has been reviewed
and outlined here.
DOI: 10.1007/s00520-013-1826-3
PMCID: PMC3699701
PMID: 23686401 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18846549 | 1. Hepatology. 2008 Dec;48(6):1932-41. doi: 10.1002/hep.22537.
Liver-specific ablation of integrin-linked kinase in mice results in abnormal
histology, enhanced cell proliferation, and hepatomegaly.
Gkretsi V(1), Apte U, Mars WM, Bowen WC, Luo JH, Yang Y, Yu YP, Orr A, St-Arnaud
R, Dedhar S, Kaestner KH, Wu C, Michalopoulos GK.
Author information:
(1)Division of Cellular and Molecular Pathology, Department of Pathology,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Hepatocyte differentiation and proliferation are greatly affected by
extracellular matrix (ECM). Primary hepatocytes cultured without matrix
dedifferentiate over time, but matrix overlay quickly restores differentiation.
ECM also is critical in liver regeneration where ECM degradation and
reconstitution are steps in the regenerative process. Integrin-linked kinase
(ILK) is a cell-ECM-adhesion component implicated in cell-ECM signaling by means
of integrins. We investigated the role of ILK in whole liver by using the
LoxP/Cre model system. ILK was eliminated from the liver by mating homozygous
ILK-floxed animals with mice expressing Cre-recombinase under control of the
alpha fetoprotein enhancer and albumin promoter. After ablation of ILK, animals
are born normal. Soon after birth, however, they develop histologic
abnormalities characterized by disorderly hepatic plates, increased
proliferation of hepatocytes and biliary cells, and increased deposition of
extracellular matrix. Cell proliferation is accompanied by increased cytoplasmic
and nuclear stabilization of beta-catenin. After this transient proliferation of
all epithelial components, proliferation subsides and final liver to body weight
ratio in livers with ILK deficient hepatocytes is two times that of wild type.
Microarray analysis of gene expression during the stage of cell proliferation
shows up-regulation of integrin and matrix-related genes and a concurrent
down-regulation of differentiation-related genes. After the proliferative stage,
however, the previous trends are reversed resulting in a super-differentiated
phenotype in the ILK-deficient livers.
CONCLUSION: Our results show for the first time in vivo the significance of ILK
and hepatic ECM-signaling for regulation of hepatocyte proliferation and
differentiation.
DOI: 10.1002/hep.22537
PMCID: PMC2597430
PMID: 18846549 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflict of interest: Nothing to
report. |
http://www.ncbi.nlm.nih.gov/pubmed/11867382 | 1. Anesth Analg. 2002 Mar;94(3):597-603; table of contents. doi:
10.1097/00000539-200203000-00022.
The potency of new muscle relaxants on recombinant muscle-type acetylcholine
receptors.
Paul M(1), Kindler CH, Fokt RM, Dresser MJ, Dipp NC, Yost CS.
Author information:
(1)Department of Anesthesia and Perioperative Care, University of California,
San Francisco 94143-0542, USA.
Comment in
Anesth Analg. 2002 Nov;95(5):1459; author reply 1459. doi:
10.1097/00000539-200211000-00067.
We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR)
muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing
muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl
rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium,
vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed
in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary
RNAs. Functional channels were activated with 10 microM acetylcholine, alone or
in combination with various concentrations of the NDMRs. Currents were recorded
with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly
inhibited acetylcholine-activated currents in a dose-dependent fashion.
Potencies of rapacuronium and Org 9488 were not statistically different at
either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or
epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank
order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar
mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 >
gallamine) correlated highly with the clinical doses needed to produce 50%
twitch depression at the adductor pollicis muscle in adults. Neuromuscular
blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different
drug-receptor affinities of the tested NDMRs contribute to the differences in
clinical dose requirements of these drugs needed to achieve appropriate muscle
relaxation.
IMPLICATIONS: Potencies of nondepolarizing muscle relaxants, studied at muscle
nicotinic acetylcholine receptors expressed in a recombinant expression system,
correlate highly with the clinical doses needed in adults to produce 50% twitch
depression at the adductor pollicis muscle.
DOI: 10.1097/00000539-200203000-00022
PMID: 11867382 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24819662 | 1. Int J Gynecol Cancer. 2014 Jun;24(5):844-50. doi:
10.1097/IGC.0000000000000137.
Elmo1 helps dock180 to regulate Rac1 activity and cell migration of ovarian
cancer.
Wang J(1), Dai JM, Che YL, Gao YM, Peng HJ, Liu B, Wang H, Linghu H.
Author information:
(1)*Department of Obstetrics and Gynecology, First Affiliated Hospital of
Chongqing Medical University; and †Department of Pathology, Faculty of Basic
Medical Sciences, Chongqing Medical University, Chongqing, People's Republic of
China.
OBJECTIVE: Engulfment and cell motility 1 (Elmo1) has been reported to cooperate
with dedicator of cytokinesis 1 (Dock180) and to be linked to the invasive
phenotype of cancer cells through activating small G-protein Rac. We aimed to
study the role of Elmo1 in the malignant migration of ovarian cancer.
METHODS: Engulfment and cell motility 1 expression was evaluated in specimens
from 93 patients with serous ovarian cancer (SOC) by immunohistochemical
staining. Next, Elmo1-RNAi cells were established by validated small
interference RNAs. Cell proliferation and cell motility were observed and
compared with Dock180-RNAi cells. To confirm their synergetic contribution to
forming focal adhesion and activating Rac1, Rac1-GTP level was measured by GST
pull-down assay and immunofluorescence was used to observe focal adhesion
formation both in Elmo1-RNAi and Dock180-RNAi cells.
RESULTS: Engulfment and cell motility 1 was mainly overexpressed in high-grade
SOC tissues. Western blot analysis demonstrated that both Elmo1 and Dock180
expressions were hampered in Elmo1-RNAi cells. Compared with the negative
control, decreased colony formation and cell invasion were observed in
Elmo1-RNAi cells and Dock180-RNAi cells. Consistently, both exhibited reduced
Rac1-GTP level and inhibited focal adhesion formation.
CONCLUSIONS: Engulfment and cell motility 1 presents with synergetic action in
helping Dock180 to activate Rac1 and promote cell motility, and thus promote
untoward expansion and aggressiveness of SOC.
DOI: 10.1097/IGC.0000000000000137
PMID: 24819662 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20978102 | 1. Genome Biol Evol. 2010;2:859-69. doi: 10.1093/gbe/evq068. Epub 2010 Oct 26.
Evolutionary rates and gene dispensability associate with replication timing in
the archaeon Sulfolobus islandicus.
Flynn KM(1), Vohr SH, Hatcher PJ, Cooper VS.
Author information:
(1)Department of Molecular, Cellular, and Biomedical Sciences, University of New
Hampshire, USA.
In bacterial chromosomes, the position of a gene relative to the single origin
of replication generally reflects its replication timing, how often it is
expressed, and consequently, its rate of evolution. However, because some
archaeal genomes contain multiple origins of replication, bias in gene dosage
caused by delayed replication should be minimized and hence the substitution
rate of genes should associate less with chromosome position. To test this
hypothesis, six archaeal genomes from the genus Sulfolobus containing three
origins of replication were selected, conserved orthologs were identified, and
the evolutionary rates (dN and dS) of these orthologs were quantified. Ortholog
families were grouped by their consensus position and designated by their
proximity to one of the three origins (O1, O2, O3). Conserved orthologs were
concentrated near the origins and most variation in genome content occurred
distant from the origins. Linear regressions of both synonymous and
nonsynonymous substitution rates on distance from replication origins were
significantly positive, the rates being greatest in the region furthest from any
of the origins and slowest among genes near the origins. Genes near O1 also
evolved faster than those near O2 and O3, which suggest that this origin may
fire later in the cell cycle. Increased evolutionary rates and gene
dispensability are strongly associated with reduced gene expression caused in
part by reduced gene dosage during the cell cycle. Therefore, in this genus of
Archaea as well as in many Bacteria, evolutionary rates and variation in genome
content associate with replication timing.
DOI: 10.1093/gbe/evq068
PMCID: PMC3000693
PMID: 20978102 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19182669 | 1. Plast Reconstr Surg. 2009 Feb;123(2 Suppl):104S-113S. doi:
10.1097/PRS.0b013e318191c5a0.
Radioprotection of osteoblasts by a fractionated dose regimen and amifostine.
Wong AK(1), Mei L, Soares MA, Schönmeyr BH, Mehrara BJ.
Author information:
(1)New York, N.Y. From the Plastic and Reconstructive Service, Department of
Surgery, Memorial Sloan-Kettering Cancer Center.
BACKGROUND: Radioprotective modalities such as dose fractionation and
pharmacologic agents such as amifostine have been used to protect bone and other
types of normal tissue from the damaging effects of ionizing radiation without
significantly impacting tumor kill. To better understand the cellular mechanism
of radioprotection of osseous tissue, the authors sought to determine the effect
of dose fractionation and amifostine on isolated osteoblasts.
METHODS: Isolated primary rat calvarial osteoblasts were exposed to single or
fractionated doses of ionizing radiation both with and without amifostine
pretreatment. Endpoints included cell growth (n = 4), vascular endothelial
growth factor production as measured by enzyme-linked immunosorbent assay (n =
3), and early osteodifferentiation as measured by a quantitative alkaline
phosphatase assay (n = 3).
RESULTS: Both dose fractionation and amifostine protect osteoblasts from the
growth inhibitory effects of ionizing radiation. Fractionation but not
amifostine was protective for hypoxia-induced vascular endothelial growth factor
production (used as a surrogate marker of normal osteoblast function). Neither
fractionation nor amifostine could prevent the inhibitory effect of ionizing
radiation on normal osteoblast osteodifferentiation as measured by alkaline
phosphatase production.
CONCLUSIONS: Both dose fractionation and amifostine have valid roles as
radioprotectants for osteoblasts and can act in an additive fashion.
Radioprotection of cell growth and viability does not necessarily correlate with
preservation of normal cellular function. Combination protocols involving dose
fractionation and amifostine may be effective in radioprotection of osteoblasts
and normal osseous tissue.
DOI: 10.1097/PRS.0b013e318191c5a0
PMID: 19182669 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20824711 | 1. Int J Cancer. 2011 Jul 1;129(1):34-44. doi: 10.1002/ijc.25646. Epub 2010 Nov
3.
PRKAR1A is overexpressed and represents a possible therapeutic target in human
cholangiocarcinoma.
Loilome W(1), Juntana S, Namwat N, Bhudhisawasdi V, Puapairoj A, Sripa B, Miwa
M, Saya H, Riggins GJ, Yongvanit P.
Author information:
(1)Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon
Kaen, Thailand.
The protein kinase A regulatory subunit 1 alpha (PRKAR1A/PKAI) pathway is
overexpressed in varieties of tumors and cancer cell lines including
cholangiocarcinoma (CCA), although its role in CCA growth modulation is unclear.
In our study, we evaluated the effect of PRKAR1A/PKAI targeting on CCA cell
proliferation. Real-time PCR demonstrated an increased mRNA expression of
PRKAR1A/PKAI, whereas protein kinase A regulatory subunit 2 beta (PRKAR2B/PKAII)
was downregulated in human CCA tissues and CCA cell lines. Immunohistochemistry
of human CCA tissues revealed increased PRKAR1A with decreased PRKAR2B protein
expression. Moreover, CCA cell lines showed abundantly expressed PRKAR1A, while
lacking PRKAR2B expression. Silencing PRKAR1A expression induced growth
inhibition and apoptosis of CCA cells, with an associated decrease in
mitogen-activated protein kinases, PI3K/Akt, JAK/STAT and Wnt/β-catenin pathway
signaling. The inhibition of PKA using a PKA inhibitor and cAMP analogs also led
to a significant cell growth inhibition. In conclusion, our study reports the
overexpression as well as molecular mechanisms by which PRKAR1A/PKA regulates
human CCA cell growth. Importantly, abrogation of gene expression caused
significant CCA cell growth inhibition, oncogenic signaling and coupled
apoptosis induction, suggesting PRKAR1A's potential as a drug target for CCA
therapy.
Copyright © 2010 UICC.
DOI: 10.1002/ijc.25646
PMID: 20824711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23454549 | 1. Exp Cell Res. 2013 May 1;319(8):1124-35. doi: 10.1016/j.yexcr.2013.02.009.
Epub 2013 Feb 27.
α-actinin1 and 4 tyrosine phosphorylation is critical for stress fiber
establishment, maintenance and focal adhesion maturation.
Feng Y(1), Ngu H, Alford SK, Ward M, Yin F, Longmore GD.
Author information:
(1)Departments of Medicine, Washington University, St. Louis, MO 63110, USA.
[email protected]
In polarized, migrating cells, stress fibers are a highly dynamic network of
contractile acto-myosin structures composed of bundles of actin filaments held
together by actin cross-linking proteins such as α-actinins. As such, α-actinins
influence actin cytoskeleton organization and dynamics and focal adhesion
maturation. In response to environmental signals, α-actinins are tyrosine
phosphorylated and this affects their binding to actin stress fibers; however,
the cellular role of α-actinin tyrosine phosphorylation remains largely unknown.
We found that non-muscle α-actinin1/4 are critical for the establishment of
dorsal stress fibers and maintenance of transverse arc stress fibers. Analysis
of cells genetically depleted of α-actinin1 and 4 reveals two distinct modes for
focal adhesion maturation. An α-actinin1 or 4 dependent mode that uses dorsal
stress fiber precursors as a template for establishing focal adhesions and their
maturation, and an α-actinin-independent manner that uses transverse arc
precursors to establish focal adhesions at both ends. Focal adhesions formed in
the absence of α-actinins are delayed in their maturation, exhibit altered
morphology, have decreased amounts of Zyxin and VASP, and reduced adhesiveness
to extracellular matrix. Further rescue experiments demonstrate that the
tyrosine phosphorylation of α-actinin1 at Y12 and α-actinin4 at Y265 is critical
for dorsal stress fiber establishment, transverse arc maintenance and focal
adhesion maturation.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yexcr.2013.02.009
PMCID: PMC4142059
PMID: 23454549 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21629434 | 1. Curr Genomics. 2010 Dec;11(8):568-77. doi: 10.2174/138920210793360916.
Cytosine methyltransferases as tumor markers.
Pavlopoulou A(1), Kossida S.
Author information:
(1)Biomedical Research Foundation of the Academy of Athens, Department of
Biotechnology, Bioinformatics & Medical Informatics Team, Soranou Efesiou 4,
11527 Athens, Greece.
Changes in DNA methylation patterns is a prominent characteristic of human
tumors. Tumor cells display reduced levels of genomic DNA methylation and
site-specific CpG island hypermethylation. Methylation of CpG dinucleotides is
catalyzed by the enzyme family of DNA methyltransferases (DNMTs). In this
review, the role of DNA methylation and DNMTs as key determinants of
carcinogenesis is further elucidated. The chromatin modifying proteins that are
known to interact with DNMTs are also described. Finally, the role of DNMTs as
potential therapeutic targets is addressed.
DOI: 10.2174/138920210793360916
PMCID: PMC3078681
PMID: 21629434 |
http://www.ncbi.nlm.nih.gov/pubmed/23918241 | 1. Med Oncol. 2013;30(3):681. doi: 10.1007/s12032-013-0681-x. Epub 2013 Aug 7.
Upregulation of microRNA-203 is associated with advanced tumor progression and
poor prognosis in epithelial ovarian cancer.
Wang S(1), Zhao X, Wang J, Wen Y, Zhang L, Wang D, Chen H, Chen Q, Xiang W.
Author information:
(1)Maternal and Child Health Hospital of Hainan Province, No. 15, Long Kun Nan
Road, Haikou, 570206, Hainan, China.
MicroRNA-203 (miR-203), possessing tumor suppressive or promotive activities,
has been found to be downregulated or upregulated in different cancer types. The
purpose of this study was to investigate whether the increased expression of
miR-203 can be used as a noninvasive diagnostic and prognostic biomarker in
epithelial ovarian cancer (EOC). Real-time quantitative PCR was performed to
detect the expression levels of miR-203 in EOC tissues. The expression levels of
miR-203 were significantly higher in EOC tissues compared to adjacent
non-cancerous tissues (p < 0.001). High expression of miR-203 was observed in
65.38 % (102/156) of EOC. In addition, high miR-203 expression was found to be
closely correlated with advanced FIGO stage (p < 0.001), higher histological
grade (p = 0.02), lymph node involvement (p < 0.001), and positive recurrence
(p < 0.001). Moreover, high miR-203 expression was correlated with shorter
overall survival (p < 0.001) and shorter progression-free survival (p < 0.001)
of EOC patients. Furthermore, multivariate analysis showed that the status of
miR-203 expression was an independent predictor for both overall survival and
progression-free survival in EOC. These findings provide the convincing evidence
for the first time that the upregulation of miR-203 may serve as a novel
molecular marker to predict the aggressive tumor progression and unfavorable
prognosis of EOC patients.
DOI: 10.1007/s12032-013-0681-x
PMID: 23918241 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23295672 | 1. Nucleic Acids Res. 2013 Feb 1;41(4):2171-9. doi: 10.1093/nar/gks1355. Epub
2013 Jan 7.
Imprinting at the PLAGL1 domain is contained within a 70-kb
CTCF/cohesin-mediated non-allelic chromatin loop.
Iglesias-Platas I(1), Court F, Camprubi C, Sparago A, Guillaumet-Adkins A,
Martin-Trujillo A, Riccio A, Moore GE, Monk D.
Author information:
(1)Servicio de Neonatología, Hospital Sant Joan de Déu (HSJD), Fundació Sant
Joan de Déu, 08950 Barcelona, Spain.
Paternal duplications of chromosome 6q24, a region that contains the imprinted
PLAGL1 and HYMAI transcripts, are associated with transient neonatal diabetes
mellitus. A common feature of imprinted genes is that they tend to cluster
together, presumably as a result of sharing common cis-acting regulatory
elements. To determine the extent of this imprinted cluster in human and mouse,
we have undertaken a systematic analysis of allelic expression and DNA
methylation of the genes mapping within an ∼1.4-Mb region flanking
PLAGL1/Plagl1. We confirm that all nine neighbouring genes are biallelically
expressed in both species. In human we identify two novel paternally expressed
PLAGL1 coding transcripts that originate from unique promoter regions. Chromatin
immunoprecipitation for CTCF and the cohesin subunits RAD21 and SMC3 reveals
evolutionarily conserved binding sites within unmethylated regions ∼5 kb
downstream of the PLAGL1 differentially methylated region and within the PLAGL1
3' untranslated region (UTR). Higher-order chromatin looping occurs between
these regions in both expressing and non-expressing tissues, forming a
non-allelic chromatin loop around the PLAGL1/Plagl1 gene. In placenta and brain
tissues, we identify an additional interaction between the PLAGL1 P3/P4
promoters and the unmethylated element downstream of the PLAGL1 differentially
methylated region that we propose facilitates imprinted expression of these
alternative isoforms.
DOI: 10.1093/nar/gks1355
PMCID: PMC3575839
PMID: 23295672 [Indexed for MEDLINE] |