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http://www.ncbi.nlm.nih.gov/pubmed/20624288 | 1. Genome Biol. 2010;11(7):R72. doi: 10.1186/gb-2010-11-7-r72. Epub 2010 Jul 12.
Long noncoding RNA genes: conservation of sequence and brain expression among
diverse amniotes.
Chodroff RA(1), Goodstadt L, Sirey TM, Oliver PL, Davies KE, Green ED, Molnár Z,
Ponting CP.
Author information:
(1)Department of Physiology, Anatomy, and Genetics, Le Gros Clark Building South
Parks Road, University of Oxford, Oxford OX1 3QX, UK.
BACKGROUND: Long considered to be the building block of life, it is now apparent
that protein is only one of many functional products generated by the eukaryotic
genome. Indeed, more of the human genome is transcribed into noncoding sequence
than into protein-coding sequence. Nevertheless, whilst we have developed a deep
understanding of the relationships between evolutionary constraint and function
for protein-coding sequence, little is known about these relationships for
non-coding transcribed sequence. This dearth of information is partially
attributable to a lack of established non-protein-coding RNA (ncRNA) orthologs
among birds and mammals within sequence and expression databases.
RESULTS: Here, we performed a multi-disciplinary study of four highly conserved
and brain-expressed transcripts selected from a list of mouse long intergenic
noncoding RNA (lncRNA) loci that generally show pronounced evolutionary
constraint within their putative promoter regions and across exon-intron
boundaries. We identify some of the first lncRNA orthologs present in birds
(chicken), marsupial (opossum), and eutherian mammals (mouse), and investigate
whether they exhibit conservation of brain expression. In contrast to
conventional protein-coding genes, the sequences, transcriptional start sites,
exon structures, and lengths for these non-coding genes are all highly variable.
CONCLUSIONS: The biological relevance of lncRNAs would be highly questionable if
they were limited to closely related phyla. Instead, their preservation across
diverse amniotes, their apparent conservation in exon structure, and
similarities in their pattern of brain expression during embryonic and early
postnatal stages together indicate that these are functional RNA molecules, of
which some have roles in vertebrate brain development.
DOI: 10.1186/gb-2010-11-7-r72
PMCID: PMC2926783
PMID: 20624288 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24299503 | 1. J Med Chem. 2014 Jan 9;57(1):131-43. doi: 10.1021/jm4015263. Epub 2013 Dec 18.
Development of 1,8-naphthalimides as clathrin inhibitors.
MacGregor KA(1), Robertson MJ, Young KA, von Kleist L, Stahlschmidt W, Whiting
A, Chau N, Robinson PJ, Haucke V, McCluskey A.
Author information:
(1)Chemistry, Centre for Chemical Biology, The University of Newcastle ,
University Drive, Callaghan, New South Wales 2308 Australia.
We reported the first small molecule inhibitors of the interaction between the
clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e.,
clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet
library identified 1. Screening of an existing in-house propriety library
identified four substituted 1,8-napthalimides as ∼80-120 μM clathrin inhibitors.
Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide,
potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl
moiety was developed, and four analogues displayed comparable activity (26, 27,
28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further
four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and
10 μM, respectively. Docking studies rationalized the structure-activity
relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide,
potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal
domain-amphiphysin inhibitor reported to date.
DOI: 10.1021/jm4015263
PMID: 24299503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23028352 | 1. PLoS Genet. 2012 Sep;8(9):e1002942. doi: 10.1371/journal.pgen.1002942. Epub
2012 Sep 13.
Hominoid-specific de novo protein-coding genes originating from long non-coding
RNAs.
Xie C(1), Zhang YE, Chen JY, Liu CJ, Zhou WZ, Li Y, Zhang M, Zhang R, Wei L, Li
CY.
Author information:
(1)Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene
Research, College of Life Sciences, Peking University, Beijing, China.
Tinkering with pre-existing genes has long been known as a major way to create
new genes. Recently, however, motherless protein-coding genes have been found to
have emerged de novo from ancestral non-coding DNAs. How these genes originated
is not well addressed to date. Here we identified 24 hominoid-specific de novo
protein-coding genes with precise origination timing in vertebrate phylogeny.
Strand-specific RNA-Seq analyses were performed in five rhesus macaque tissues
(liver, prefrontal cortex, skeletal muscle, adipose, and testis), which were
then integrated with public transcriptome data from human, chimpanzee, and
rhesus macaque. On the basis of comparing the RNA expression profiles in the
three species, we found that most of the hominoid-specific de novo
protein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or
chimpanzee with a similar transcript structure and correlated tissue expression
profile. According to the rule of parsimony, the majority of these
hominoid-specific de novo protein-coding genes appear to have acquired a
regulated transcript structure and expression profile before acquiring coding
potential. Interestingly, although the expression profile was largely
correlated, the coding genes in human often showed higher transcriptional
abundance than their non-coding counterparts in rhesus macaque. The major
findings we report in this manuscript are robust and insensitive to the
parameters used in the identification and analysis of de novo genes. Our results
suggest that at least a portion of long non-coding RNAs, especially those with
active and regulated transcription, may serve as a birth pool for protein-coding
genes, which are then further optimized at the transcriptional level.
DOI: 10.1371/journal.pgen.1002942
PMCID: PMC3441637
PMID: 23028352 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21622663 | 1. Bioinformatics. 2011 Jul 15;27(14):1894-900. doi:
10.1093/bioinformatics/btr314. Epub 2011 May 26.
Computational discovery of human coding and non-coding transcripts with
conserved splice sites.
Rose D(1), Hiller M, Schutt K, Hackermüller J, Backofen R, Stadler PF.
Author information:
(1)Bioinformatics Group, Department of Computer Science, University of Leipzig,
Leipzig, Germany. [email protected]
MOTIVATION: Long non-coding RNAs (lncRNAs) resemble protein-coding mRNAs but do
not encode proteins. Most lncRNAs are under lower sequence constraints than
protein-coding genes and lack conserved secondary structures, making it hard to
predict them computationally.
RESULTS: We introduce an approach to predict spliced lncRNAs in vertebrate
genomes combining comparative genomics and machine learning. It is based on
detecting signatures of characteristic splice site evolution in vertebrate whole
genome alignments. First, we predict individual splice sites, then assemble
compatible sites into exon candidates, and finally predict multi-exon
transcripts. Using a novel method to evaluate typical splice site substitution
patterns that explicitly takes the species phylogeny into account, we show that
individual splice sites can be accurately predicted. Since our approach relies
only on predicted splice sites, it can uncover both coding and non-coding exons.
We show that our predicted exons and partial transcripts are mostly non-coding
and lack conserved secondary structures. These exons are of particular interest,
since existing computational approaches cannot detect them. Transcriptome
sequencing data indicate tissue-specific expression patterns of predicted exons
and there is evidence that increasing sequencing depth and breadth will validate
additional predictions. We also found a significant enrichment of predicted
exons that form multi-exon transcript parts, and we experimentally validate such
a novel multi-exon gene. Overall, we obtain 336 novel multi-exon transcript
predictions from human intergenic regions. Our results indicate the existence of
novel human transcripts that are conserved in evolution and our approach
contributes to the completion of the human transcript catalog.
AVAILABILITY AND IMPLEMENTATION: Predicted human splice sites, exons and gene
structures together with a Perl implementation of the tree-based log-odds
scoring and a supplementary PDF file containing additional figures and tables
are available at:
http://www.bioinf.uni-leipzig.de/publications/supplements/10-010. The five
experimentally confirmed partial transcript isoforms have been deposited in
GenBank under accession numbers HM587422-HM587426.
DOI: 10.1093/bioinformatics/btr314
PMID: 21622663 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21252793 | 1. Obstet Gynecol. 2011 Feb;117(2 Pt 2):470-472. doi:
10.1097/AOG.0b013e3181fd2e38.
2009 pandemic influenza A (H1N1) and vaccine failure in pregnancy.
Louie JK(1), Wadford DA, Norman A, Jamieson DJ.
Author information:
(1)From the California Department of Public Health, Richmond, California; the
Sacramento County Department of Health and Human Services, Sacramento,
California; and the National Center for Chronic Disease Prevention and Health
Promotion and the Centers for Disease Control and Prevention, Atlanta, Georgia.
BACKGROUND: Emerging data suggest that pregnancy conveys high risk for severe
complications from the 2009 pandemic influenza A virus (2009 H1N1) infection.
CASE: We describe an infected pregnant woman with critical illness owing to
acute respiratory distress syndrome despite previous vaccination. Early
serologic testing indicated absent immunity, followed 11 days later by a robust
immune response. The patient required mechanical ventilation for 11 days, but
ultimately improved, and was discharged home on hospital day 14.
CONCLUSION: With the expectation that 2009 H1N1 will continue to cause disease
in the immediate future, the virus has been included as a component of the
2010-2011 seasonal influenza vaccine. Vaccination of pregnant women is strongly
encouraged. However, regardless of vaccination history, clinicians should remain
vigilant for 2009 H1N1 infection when the virus is in circulation, and should
not delay antiviral treatment of pregnant women with suspected influenza.
DOI: 10.1097/AOG.0b013e3181fd2e38
PMID: 21252793 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22030045 | 1. Taiwan J Obstet Gynecol. 2011 Sep;50(3):312-7. doi:
10.1016/j.tjog.2010.07.002.
Pandemic influenza H1N1 2009 virus infection in pregnancy in Turkey.
Ozyer S(1), Unlü S, Celen S, Uzunlar O, Saygan S, Su FA, Beşli M, Danışman N,
Mollamahmutoğlu L.
Author information:
(1)Department of Obstetrics and Gynecology, Zekai Tahir Burak Women's Health
Education and Research Hospital, Ankara, Turkey. [email protected]
OBJECTIVES: To describe the clinical characteristics of the pregnant women who
were hospitalized in a tertiary referral hospital with pandemic influenza H1N1
2009 virus infection and neonatal outcomes from October 2009 to December 2009
during which the pandemic influenza cases peaked in Turkey.
MATERIALS AND METHODS: Twenty-five pregnant women who were hospitalized with
influenza-like illness and who had laboratory confirmation for pandemic
influenza H1N1 virus infection were evaluated prospectively.
RESULTS: Of the 25 patients, 4 (16%) were in the first trimester, 8 (32%) were
in the second trimester, and 13 (52%) were in the third trimester. The median
time from the onset of symptoms to the initiation of antiviral therapy was 1 day
(range 1-9 days). Nineteen (76%) patients received oseltamivir treatment. It
took 1.6 days on the average for the fever defervescence after the initiation of
treatment or hospitalization. Of the 14 patients who underwent chest
radiography, three had findings consistent with pneumonia. The mean duration of
hospitalization was 4.8 days. Four women (16%) were admitted to an intensive
care unit, but there were no maternal or neonatal deaths in this series. At the
time of their H1N1 hospitalization, seven women delivered by cesarean at 33-40
weeks gestation, two vaginally at 38 weeks gestation, and two had an abortion at
10 weeks and 16 weeks of gestation, respectively. None of the infants had any
evidence of influenza infection.
CONCLUSION: Pregnant women are at increased risk for complications from pandemic
influenza H1N1 virus infection. Timely medical attention with early recourse to
antiviral therapy is associated with a better outcome in H1N1-affected pregnant
women.
Copyright © 2011. Published by Elsevier B.V.
DOI: 10.1016/j.tjog.2010.07.002
PMID: 22030045 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20587619 | 1. RNA. 2010 Aug;16(8):1478-87. doi: 10.1261/rna.1951310. Epub 2010 Jun 29.
Genome-wide computational identification and manual annotation of human long
noncoding RNA genes.
Jia H(1), Osak M, Bogu GK, Stanton LW, Johnson R, Lipovich L.
Author information:
(1)Center for Molecular Medicine and Genetics, Wayne State University, Detroit,
MO 48202, USA.
Experimental evidence suggests that half or more of the mammalian transcriptome
consists of noncoding RNA. Noncoding RNAs are divided into short noncoding RNAs
(including microRNAs) and long noncoding RNAs (lncRNAs). We defined
complementary DNAs (cDNAs) lacking any positive-strand open reading frames
(ORFs) longer than 30 amino acids, as well as cDNAs lacking any evidence of
interspecies conservation of their longer-than-30-amino acid ORFs, as noncoding.
We have identified 5446 lncRNA genes in the human genome from approximately
24,000 full-length cDNAs, using our new ORF-prediction pipeline. We combined
them nonredundantly with lncRNAs from four published sources to derive 6736
lncRNA genes. In an effort to distinguish standalone and antisense lncRNA genes
from database artifacts, we stratified our catalog of lncRNAs according to the
distance between each lncRNA gene candidate and its nearest known protein-coding
gene. We concurrently examined the protein-coding capacity of known genes
overlapping with lncRNAs. Remarkably, 62% of known genes with "hypothetical
protein" names actually lacked protein-coding capacity. This study has greatly
expanded the known human lncRNA catalog, increased its accuracy through manual
annotation of cDNA-to-genome alignments, and revealed that a large set of
hypothetical-protein genes in GenBank lacks protein-coding capacity. In
addition, we have developed, independently of existing NCBI tools, command-line
programs with high-throughput ORF-finding and BLASTP-parsing functionality,
suitable for future automated assessments of protein-coding capacity of novel
transcripts.
DOI: 10.1261/rna.1951310
PMCID: PMC2905748
PMID: 20587619 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20428234 | 1. PLoS One. 2010 Apr 23;5(4):e10316. doi: 10.1371/journal.pone.0010316.
Mining mammalian transcript data for functional long non-coding RNAs.
Khachane AN(1), Harrison PM.
Author information:
(1)Department of Biology, McGill University, Montreal, Quebec, Canada.
[email protected]
BACKGROUND: The role of long non-coding RNAs (lncRNAs) in controlling gene
expression has garnered increased interest in recent years. Sequencing projects,
such as Fantom3 for mouse and H-InvDB for human, have generated abundant data on
transcribed components of mammalian cells, the majority of which appear not to
be protein-coding. However, much of the non-protein-coding transcriptome could
merely be a consequence of 'transcription noise'. It is therefore essential to
use bioinformatic approaches to identify the likely functional candidates in a
high throughput manner.
PRINCIPAL FINDINGS: We derived a scheme for classifying and annotating likely
functional lncRNAs in mammals. Using the available experimental full-length cDNA
data sets for human and mouse, we identified 78 lncRNAs that are either
syntenically conserved between human and mouse, or that originate from the same
protein-coding genes. Of these, 11 have significant sequence homology. We found
that these lncRNAs exhibit: (i) patterns of codon substitution typical of
non-coding transcripts; (ii) preservation of sequences in distant mammals such
as dog and cow, (iii) significant sequence conservation relative to their
corresponding flanking regions (in 50% cases, flanking regions do not have
homology at all; and in the remaining, the degree of conservation is
significantly less); (iv) existence mostly as single-exon forms (8/11); and, (v)
presence of conserved and stable secondary structure motifs within them. We
further identified orthologous protein-coding genes that are contributing to the
pool of lncRNAs; of which, genes implicated in carcinogenesis are significantly
over-represented.
CONCLUSION: Our comparative mammalian genomics approach coupled with
evolutionary analysis identified a small population of conserved long
non-protein-coding RNAs (lncRNAs) that are potentially functional across
Mammalia. Additionally, our analysis indicates that amongst the orthologous
protein-coding genes that produce lncRNAs, those implicated in cancer
pathogenesis are significantly over-represented, suggesting that these lncRNAs
could play an important role in cancer pathomechanisms.
DOI: 10.1371/journal.pone.0010316
PMCID: PMC2859052
PMID: 20428234 [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/22707570 | 1. Genome Res. 2012 Dec;22(12):2529-40. doi: 10.1101/gr.140475.112. Epub 2012 Jun
15.
Long noncoding RNAs in C. elegans.
Nam JW(1), Bartel DP.
Author information:
(1)Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142,
USA.
Thousands of long noncoding RNAs (lncRNAs) have been found in vertebrate
animals, a few of which have known biological roles. To better understand the
genomics and features of lncRNAs in invertebrates, we used available RNA-seq,
poly(A)-site, and ribosome-mapping data to identify lncRNAs of Caenorhabditis
elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or
multiexonic structures that did not overlap protein-coding transcripts, and
about sixty antisense lncRNAs (ancRNAs), which were complementary to
protein-coding transcripts. Compared to protein-coding genes, the lncRNA genes
tended to be expressed in a stage-dependent manner. Approximately 25% of the
newly identified lincRNAs showed little signal for sequence conservation and
mapped antisense to clusters of endogenous siRNAs, as would be expected if they
serve as templates and targets for these siRNAs. The other 75% tended to be more
conserved and included lincRNAs with intriguing expression and sequence features
associating them with processes such as dauer formation, male identity, sperm
formation, and interaction with sperm-specific mRNAs. Our study provides a
glimpse into the lncRNA content of a nonvertebrate animal and a resource for
future studies of lncRNA function.
DOI: 10.1101/gr.140475.112
PMCID: PMC3514682
PMID: 22707570 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20020530 | 1. Hum Mutat. 2010 Feb;31(2):E1146-62. doi: 10.1002/humu.21183.
NKX2-1 mutations leading to surfactant protein promoter dysregulation cause
interstitial lung disease in "Brain-Lung-Thyroid Syndrome".
Guillot L(1), Carré A, Szinnai G, Castanet M, Tron E, Jaubert F, Broutin I,
Counil F, Feldmann D, Clement A, Polak M, Epaud R.
Author information:
(1)INSERM UMR 938, UPMC, Université Paris 6, France.
NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the
surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We
identified and functionally characterized two new de novo NKX2-1 mutations
c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar
severe interstitial lung disease (ILD), hypotonia, and congenital
hypothyroidism. Functional analyses using A549 and HeLa cells revealed that
NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a
dominant negative effect on wild-type (WT) NKX2-1. In contrast,NKX2-1-p.R165W
activated SFTPC, to a significantly greater extent than did WTNKX2-1, while
SFTPB activation was only significantly reduced in HeLa cells. In accordance
with our in vitro data, we found decreased amounts of SP-B and SP-C by western
blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of
altered surfactant protein metabolism on lung histology (patient with
NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was
associated with altered surfactant protein metabolism, and both gain and loss of
function of the mutated NKX2-1 genes on surfactant protein promoters were
associated with ILD in "Brain-Lung-Thyroid syndrome".
(c) 2009 Wiley-Liss, Inc.
DOI: 10.1002/humu.21183
PMID: 20020530 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22272853 | 1. S Afr Med J. 2011 Sep 27;101(10):744.
Pregnancy and H1N1 influenza: lessons to learn.
Moodley J, Blumberg L, Schoub BD.
Pregnancy, with or without additional complications, constitutes a high-risk
condition for complications of influenza infection and warrants early
intervention with neuraminidase inhibitors such as oseltamivir, if influenza is
suspected. Treatment should not be delayed for laboratory confirmation. In South
Africa, the high burden of HIV infection is a further complication.
PMID: 22272853 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17333874 | 1. Nurs Times. 2007 Feb 20-26;103(8):28-9.
Use of tens in pain management: part two--how to use tens.
Poole D(1).
Author information:
(1)Royal Hallamshire Hospital, Sheffield.
Transcutaneous electrical nerve stimulation is widely used in pain management
but its effectiveness depends on the stimulation being targeted appropriately.
This article, the second in a two-part series, outlines how to set up and use a
TENS machine to achieve the most effective results.
PMID: 17333874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23467584 | 1. Int J Nanomedicine. 2013;8:899-908. doi: 10.2147/IJN.S38641. Epub 2013 Feb 28.
Cancer stem cell theory: therapeutic implications for nanomedicine.
Wang K(1), Wu X, Wang J, Huang J.
Author information:
(1)Cancer Institute (Key Laboratory of Cancer Prevention and Intervention,
National Ministry of Education; Provincial Key Laboratory of Molecular Biology
in Medical Sciences), Hangzhou, People's Republic of China.
Evidence continues to accumulate showing that tumors contain a minority
population of cells responsible for tumor initiation, growth, and recurrence.
These are termed "cancer stem cells" (CSCs). Functional assays have identified
the self-renewal and tumor-initiation capabilities of CSCs. Moreover, recent
studies have revealed that these CSCs is responsible for chemotherapy resistance
within a tumor. Several mechanisms of chemoresistance have been proposed,
including increased Wnt/β-catenin and Notch signaling, as well as high
expression levels of adenosine triphosphate-binding cassette transporters, an
active DNA repair capacity, and slow rate of self-renewal. Nanoscale
drug-delivery systems, which transport therapeutically active molecules, prolong
circulation, and improve biodistribution in the body, may allow more effective
and specific therapies to address the challenges posed by CSCs. In particular,
some nanovehicles are being exploited for selective drug delivery to CSCs and
show promising results. In this review, we highlight the mechanisms of drug
resistance and the novel strategies using nanoscale drugs to eliminate CSCs.
DOI: 10.2147/IJN.S38641
PMCID: PMC3589204
PMID: 23467584 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21208905 | 1. Clin Cancer Res. 2011 Jan 1;17(1):111-21. doi: 10.1158/1078-0432.CCR-10-2075.
Neural tumor-initiating cells have distinct telomere maintenance and can be
safely targeted for telomerase inhibition.
Castelo-Branco P(1), Zhang C, Lipman T, Fujitani M, Hansford L, Clarke I, Harley
CB, Tressler R, Malkin D, Walker E, Kaplan DR, Dirks P, Tabori U.
Author information:
(1)The Arthur and Sonia Labatt Brain Tumor Research Centre, Cell Biology
Program, The Hospital for Sick Children, University of Toronto, Toronto,
Ontario, Canada.
Comment in
Clin Cancer Res. 2011 Jan 1;17(1):3-5. doi: 10.1158/1078-0432.CCR-10-2686.
PURPOSE: Cancer recurrence is one of the major setbacks in oncology. Maintaining
telomeres is essential for sustaining the limitless replicative potential of
such cancers. Because telomerase is thought to be active in all tumor cells and
normal stem cells, telomerase inhibition may be nonspecific and have detrimental
effects on tissue maintenance and development by affecting normal stem cell
self-renewal.
METHODS: We examined telomerase activity, telomere maintenance, and stem cell
maturation in tumor subpopulations from freshly resected gliomas, long-term,
primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell
lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on
propagation and self-renewal capacity of TIC and normal stem cells in vitro and
in vivo.
RESULTS: Telomerase was undetectable in the majority of tumor cells and specific
to the TIC subpopulation that possessed critically short telomeres. In contrast,
normal tissue stem cells had longer telomeres and undetectable telomerase
activity and were insensitive to telomerase inhibition, which results in
proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant
survival benefit and late tumor growth arrest of neuroblastoma TIC were observed
in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible
loss of self-renewal and stem cell capabilities even after cessation of
treatment in vitro and in vivo.
CONCLUSIONS: TIC exhaustion with telomerase inhibition and lack of telomerase
dependency in normal stem cells add new dimensions to the telomere hypothesis
and suggest that targeting TIC with telomerase inhibitors may represent a
specific and safe therapeutic approach for tumors of neural origin.
©2011 AACR.
DOI: 10.1158/1078-0432.CCR-10-2075
PMID: 21208905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20232321 | 1. Chem Biodivers. 2010 Mar;7(3):477-93. doi: 10.1002/cbdv.200900187.
Oligonucleotide n3'-->p5' phosphoramidates and thio-phoshoramidates as potential
therapeutic agents.
Gryaznov SM(1).
Author information:
(1)Geron Corporation, 230 Constitution Drive, Menlo Park, CA 94025, USA.
[email protected]
Nucleic acids analogues, i.e., oligonucleotide N3'-->P5' phosphoramidates and
N3'-->P5' thio-phosphoramidates, containing 3'-amino-3'-deoxy nucleosides with
various 2'-substituents were synthesized and extensively studied. These
compounds resist nuclease hydrolysis and form stable duplexes with complementary
native phosphodiester DNA and, particularly, RNA strands. An increase in
duplexes' melting temperature, DeltaT(m), relative to their phosphodiester
counterparts, reaches 2.2-4.0 degrees per modified nucleoside. 2'-OH-
(RNA-like), 2'-O-Me-, and 2'-ribo-F-nucleoside substitutions result in the
highest degree of duplex stabilization. Moreover, under close to physiological
salt and pH conditions, the 2'-deoxy- and 2'-fluoro-phosphoramidate compounds
form extremely stable triple-stranded complexes with either single- or
double-stranded phosphodiester DNA oligonucleotides. Melting temperature, T(m),
of these triplexes exceeds T(m) values for the isosequential phosphodiester
counterparts by up to 35 degrees . 2'-Deoxy-N3'-->P5' phosphoramidates adopt
RNA-like C3'-endo or N-type nucleoside sugar-ring conformations and hence can be
used as stable RNA mimetics. Duplexes formed by 2'-deoxy phosphoramidates with
complementary RNA strands are not substrates for RNase H-mediated cleavage in
vitro. Oligonucleotide phosphoramidates and especially thio-phosphoramidates
conjugated with lipid groups are cell-permeable and demonstrate high biological
target specific activity in vitro. In vivo, these compounds show good
bioavailability and efficient biodistribution to all major organs, while
exerting acceptable toxicity at therapeutically relevant doses. Short
oligonucleotide N3'-->P5' thio-phosphoramidate conjugated to 5'-palmitoyl group,
designated as GRN163L (Imetelstat), was recently introduced as a potent human
telomerase inhibitor. GRN163L is not an antisense agent; it is a direct
competitive inhibitor of human telomerase, which directly binds to the active
site of the enzyme and thus inhibits its activity. This compound is currently in
multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum
anticancer agent.
DOI: 10.1002/cbdv.200900187
PMID: 20232321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24257253 | 1. J Vet Med Sci. 2014 Mar;76(3):377-87. doi: 10.1292/jvms.13-0512. Epub 2013 Nov
20.
Demonstration of the clathrin- and caveolin-mediated endocytosis at the
maternal-fetal barrier in mouse placenta after intravenous administration of
gold nanoparticles.
Rattanapinyopituk K(1), Shimada A, Morita T, Sakurai M, Asano A, Hasegawa T,
Inoue K, Takano H.
Author information:
(1)Department of Veterinary Pathology, Tottori University, 4-101 Koyama Minami,
Tottori 680-8553, Japan.
Exposure to nanoparticles during pregnancy is a public concern, because
nanoparticles may pass from the mother to the fetus across the placenta. The
purpose of this study was to determine the possible translocation pathway of
gold nanoparticles across the maternal-fetal barrier as well as the toxicity of
intravenously administered gold nanoparticles to the placenta and fetus.
Pregnant ICR mice were intravenously injected with 0.01% of 20- and 50-nm gold
nanoparticle solutions on the 16th and 17th days of gestation. There was no sign
of toxic damage to the placentas as well as maternal and fetal organs of the
mice treated with 20- and 50-nm gold nanoparticles. ICP-MS analysis demonstrated
significant amounts of gold deposited in the maternal livers and placentas, but
no detectable level of gold in the fetal organs. However, electron microscopy
demonstrated an increase of endocytic vesicles in the cytoplasm of
syncytiotrophoblasts and fetal endothelial cells in the maternal-fetal barrier
of mice treated with gold nanoparticles. Clathrin immunohistochemistry and
immunoblotting showed increased immunoreactivity of clathrin protein in the
placental tissues of mice treated with 20- and 50-nm gold nanoparticles;
clathrin immunopositivity was observed in syncytiotrophoblasts and fetal
endothelial cells. In contrast, caveolin-1 immunopositivity was observed
exclusively in the fetal endothelium. These findings suggested that intravenous
administration of gold nanoparticles may upregulate clathrin- and
caveolin-mediated endocytosis at the maternal-fetal barrier in mouse placenta.
DOI: 10.1292/jvms.13-0512
PMCID: PMC4013364
PMID: 24257253 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21062983 | 1. Cancer Res. 2010 Nov 15;70(22):9494-504. doi: 10.1158/0008-5472.CAN-10-0233.
Epub 2010 Nov 9.
The telomerase inhibitor imetelstat depletes cancer stem cells in breast and
pancreatic cancer cell lines.
Joseph I(1), Tressler R, Bassett E, Harley C, Buseman CM, Pattamatta P, Wright
WE, Shay JW, Go NF.
Author information:
(1)Geron Corporation, Menlo Park, California 94025, USA. [email protected]
Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to
be responsible for the maintenance and recurrence of cancer and metastasis.
Telomerase is constitutively active in both bulk tumor cell and CSC populations
but has only limited expression in normal tissues. Thus, inhibition of
telomerase has been shown to be a viable approach in controlling cancer growth
in nonclinical studies and is currently in phase II clinical trials. In this
study, we investigated the effects of imetelstat (GRN163L), a potent telomerase
inhibitor, on both the bulk cancer cells and putative CSCs. When breast and
pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase
activity in the bulk tumor cells and CSC subpopulations were inhibited.
Additionally, imetelstat treatment reduced the CSC fractions present in the
breast and pancreatic cell lines. In vitro treatment with imetelstat, but not
control oligonucleotides, also reduced the proliferation and self-renewal
potential of MCF7 mammospheres and resulted in cell death after <4 weeks of
treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in
nude mice, concomitant with a reduction in the CSC levels. Differences between
telomerase activity expression levels or telomere length of CSCs and bulk tumor
cells in these cell lines did not correlate with the increased sensitivity of
CSCs to imetelstat, suggesting a mechanism of action independent of telomere
shortening for the effects of imetelstat on the CSC subpopulations. Our results
suggest that imetelstat-mediated depletion of CSCs may offer an alternative
mechanism by which telomerase inhibition may be exploited for cancer therapy.
Copyright © 2010 AACR.
DOI: 10.1158/0008-5472.CAN-10-0233
PMID: 21062983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24327604 | 1. Oncotarget. 2013 Dec;4(12):2186-207. doi: 10.18632/oncotarget.1497.
Drug resistance in multiple myeloma: latest findings and new concepts on
molecular mechanisms.
Abdi J(1), Chen G, Chang H.
Author information:
(1)Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Ontario,
Canada.
Erratum in
Oncotarget. 2015 Apr 10;6(10):7364.
Oncotarget. 2015 Apr 10;6(10):7364. doi: 10.18632/oncotarget.3810.
In the era of new and mostly effective therapeutic protocols, multiple myeloma
still tends to be a hard-to-treat hematologic cancer. This hallmark of the
disease is in fact a sequel to drug resistant phenotypes persisting initially or
emerging in the course of treatment. Furthermore, the heterogeneous nature of
multiple myeloma makes treating patients with the same drug challenging because
finding a drugable oncogenic process common to all patients is not yet feasible,
while our current knowledge of genetic/epigenetic basis of multiple myeloma
pathogenesis is outstanding. Nonetheless, bone marrow microenvironment
components are well known as playing critical roles in myeloma tumor cell
survival and environment-mediated drug resistance happening most possibly in all
myeloma patients. Generally speaking, however; real mechanisms underlying drug
resistance in multiple myeloma are not completely understood. The present review
will discuss the latest findings and concepts in this regard. It reviews the
association of important chromosomal translocations, oncogenes (e.g. TP53)
mutations and deranged signaling pathways (e.g. NFκB) with drug response in
clinical and experimental investigations. It will also highlight how bone marrow
microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could
contribute to drug resistance in multiple myeloma.
DOI: 10.18632/oncotarget.1497
PMCID: PMC3926819
PMID: 24327604 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22382179 | 1. Indian J Med Res. 2012;135(1):26-30. doi: 10.4103/0971-5916.93420.
Expression of telomerase & its significance in the diagnosis of pancreatic
cancer.
Zisuh AV(1), Han TQ, Zhan SD.
Author information:
(1)Department of General Surgery, Ruijin Hospital affiliated to Shanghai
Jiaotong, University School of Medicine, Sinan Road, PR of China.
Pancreatic cancer has one of the worst prognoses among all types of cancers. The
survival rate is less than 5 per cent; this is due to difficulty in diagnosing
at an early stage. Despite the improvements in diagnostic imaging techniques
such as computed tomography, magnetic resonance imaging, etc., the early
diagnosis of pancreatic cancer is still difficult. Alternative methods of
diagnosing pancreatic cancer at an early stage are presently been explored. The
detection of telomerase activity has been proposed to be a useful tool in the
diagnosis of pancreatic cancer. Telomerase is made up of three major parts
namely, human telomerase reverse transcriptase, human telomerase and telomerase
-associated protein. Several researchers have shown telomerase activity in
tissues and fluids of patients with pancreatic and other types of cancers. About
95 per cent telomerase activity has been detected in pancreatic adenocarcinoma.
Since telomerase activity is present in a vast majority of human cancers, it
might have a role in the diagnosis and treatment of cancer.
DOI: 10.4103/0971-5916.93420
PMCID: PMC3307179
PMID: 22382179 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23272238 | 1. PLoS One. 2012;7(12):e52335. doi: 10.1371/journal.pone.0052335. Epub 2012 Dec
18.
Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain
cancer model with decreased sensitivity to histone deacetylase inhibition.
Smith SJ(1), Wilson M, Ward JH, Rahman CV, Peet AC, Macarthur DC, Rose FR,
Grundy RG, Rahman R.
Author information:
(1)Children's Brain Tumour Research Centre, School of Clinical Sciences,
University of Nottingham, Nottingham, United Kingdom.
INTRODUCTION: Physiologically relevant pre-clinical ex vivo models
recapitulating CNS tumor micro-environmental complexity will aid development of
biologically-targeted agents. We present comprehensive characterization of tumor
aggregates generated using the 3D Rotary Cell Culture System (RCCS).
METHODS: CNS cancer cell lines were grown in conventional 2D cultures and the
RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted
by genome wide gene expression and microRNA arrays, coupled with
immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug
sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat.
RESULTS: Macroscopic RCCS aggregates recapitulated the heterogeneous morphology
of brain tumors with a distinct proliferating rim, necrotic core and oxygen
tension gradient. Gene expression and microRNA analyses revealed significant
differences with 3D expression intermediate to 2D cultures and primary brain
tumors. Metabolic profiling revealed differential profiles, with an increase in
tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a
drug testing tool, we determined the efficacy of Vorinostat against aggregates
of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced
sensitivity when assaying in 3D culture conditions compared to classical 2D drug
screen approaches.
CONCLUSIONS: Our comprehensive characterization demonstrates that 3D RCCS
culture of high grade brain tumor cells has profound effects on the genetic,
epigenetic and metabolic profiles of cultured cells, with these cells residing
as an intermediate phenotype between that of 2D cultures and primary tumors.
There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS
partially re-capitulates tissue specific features, allowing drug testing in a
more relevant ex vivo system.
DOI: 10.1371/journal.pone.0052335
PMCID: PMC3525561
PMID: 23272238 [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/21332640 | 1. J Cell Mol Med. 2011 Jul;15(7):1433-42. doi: 10.1111/j.1582-4934.2011.01279.x.
Targeting telomerase-expressing cancer cells.
Ouellette MM(1), Wright WE, Shay JW.
Author information:
(1)Eppley Institute for Research in Cancer, University of Nebraska Medical
Center, Omaha, NE, USA.
The role of telomeres and telomerase as a target for cancer therapeutics is an
area of continuing interest. This review is intended to provide an update on the
field, pointing to areas in which our knowledge remains deficient and exploring
the details of the most promising areas being advanced into clinical trials.
Topics that will be covered include the role of dysfunctional telomeres in
cellular aging and how replicative senescence provides an initial barrier to the
emergence of immortalized cells, a hallmark of cancer. As an important
translational theme, this review will consider possibilities for selectively
targeting telomeres and telomerase to enhance cancer therapy. The role of
telomerase as an immunotherapy, as a gene therapy approach using telomerase
promoter driven oncolytic viruses and as a small oligonucleotide targeted
therapy (Imetelstat) will be discussed.
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation
for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
DOI: 10.1111/j.1582-4934.2011.01279.x
PMCID: PMC3370414
PMID: 21332640 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25584909 | 1. Allergy Asthma Proc. 2014 Nov-Dec;35(6):429-34. doi: 10.2500/aap.2014.35.3798.
Atopic dermatitis: the updated practice parameter and beyond.
Boguniewicz M(1).
Author information:
(1)Division of Allergy-Immunology, Department of Pediatrics, National Jewish
Health and University of Colorado School of Medicine Denver, Colorado, USA.
An update to the atopic dermatitis (AD) practice parameter was published in 2013
using an established grading system for determining category of evidence and
strength of recommendation. Since the previous update in 2004, a number of
seminal observations regarding skin barrier and immune dysregulation in AD have
been made with important therapeutic implications. A key addition to the
treatment algorithm based on our understanding that normal-appearing skin in
patients with AD is not normal is proactive therapy. Studies with both topical
steroids and a topical calcineurin inhibitor have shown that in patients with
relapsing AD, if they are able to clear or almost clear their eczema, then
twice-weekly proactive treatment of normal-appearing skin that tends to flare
leads to better disease control. For difficult-to-manage patients, the value of
wet wrap therapy is reaffirmed in the practice parameter update. In addition,
allergen immunotherapy is now a consideration in select patients with AD and
aeroallergen sensitivity. Beyond the practice parameter, novel approaches to
filaggrin deficiency are being evaluated. With respect to immune dysregulation,
dupilumab, a fully human monoclonal antibody directed at the IL-4 receptor alpha
subunit was recently shown to be effective in treating adults with
moderate-to-severe AD.
DOI: 10.2500/aap.2014.35.3798
PMID: 25584909 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23386830 | 1. Front Pharmacol. 2013 Jan 31;4:5. doi: 10.3389/fphar.2013.00005. eCollection
2013.
Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.
Davidson D(1), Amrein L, Panasci L, Aloyz R.
Author information:
(1)Department of Oncology, Segal Cancer Centre, Lady Davis Institute for Medical
Research, Jewish General Hospital, McGill University Montreal, QC, Canada.
Many current chemotherapies function by damaging genomic DNA in rapidly dividing
cells ultimately leading to cell death. This therapeutic approach differentially
targets cancer cells that generally display rapid cell division compared to
normal tissue cells. However, although these treatments are initially effective
in arresting tumor growth and reducing tumor burden, resistance and disease
progression eventually occur. A major mechanism underlying this resistance is
increased levels of cellular DNA repair. Most cells have complex mechanisms in
place to repair DNA damage that occurs due to environmental exposures or normal
metabolic processes. These systems, initially overwhelmed when faced with
chemotherapy induced DNA damage, become more efficient under constant selective
pressure and as a result chemotherapies become less effective. Thus, inhibiting
DNA repair pathways using target specific small molecule inhibitors may overcome
cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a
major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated
in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK).
The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and
recruiting other repair molecules. It also has enzymatic activity that may be
involved in DNA damage signaling. Because of its' central role in repair of
DSBs, DNA-PK has been the focus of a number of small molecule studies. In these
studies specific DNA-PK inhibitors have shown efficacy in synergizing
chemotherapies in vitro. However, compounds currently known to specifically
inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor
solubility and have high metabolic lability in vivo leading to short serum
half-lives. Future improvement in DNA-PK inhibition will likely be achieved by
designing new molecules based on the recently reported crystallographic
structure of DNA-PK. Computer based drug design will not only assist in
identifying novel functional moieties to replace the metabolically labile
morpholino group but will also facilitate the design of molecules to target the
DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.
DOI: 10.3389/fphar.2013.00005
PMCID: PMC3560216
PMID: 23386830 |
http://www.ncbi.nlm.nih.gov/pubmed/24275927 | 1. Curr Opin Pulm Med. 2014 Jan;20(1):87-94. doi: 10.1097/MCP.0000000000000007.
Monoclonal antibodies for the treatment of refractory asthma.
Hambly N(1), Nair P.
Author information:
(1)Division of Respirology, Department of Medicine, St Joseph's Healthcare and
McMaster University, Hamilton, Ontario, Canada.
PURPOSE OF REVIEW: A small proportion of patients with asthma have severe
disease characterized by persistent airflow obstruction, airway
hyperresponsiveness and eosinophilic airway inflammation. This review focuses on
the clinical efficacy of inhibiting T helper 2-cytokine-mediated inflammatory
responses using monoclonal antibodies directed against immunoglobulin E (IgE),
interleukin (IL)-5, and IL-4/IL-13 in patients with severe refractory asthma.
RECENT FINDINGS: The heterogeneity of airway inflammation in severe asthma has
led to the recognition of multiple pathophysiologically distinct severe asthma
endotypes. Biomarkers are being developed and evaluated to identify these
endotypes and to guide the use of specific biologics in the appropriate patients
who remain uncontrolled on high doses of inhaled corticosteroids and long-acting
bronchodilators or oral corticosteroids. Examples include the efficacy of
omalizumab in patients with severe refractory atopic asthma characterized by
raised serum total IgE, mepolizumab, reslizumab, and benralizumab in patients
with recurrent eosinophilic exacerbations characterized by blood and sputum
eosinophilia despite high doses of corticosteroids, and lebrikizumab,
pitrakinra, dupilumab, and tralokinumab that target the IL-4/IL-13 signalling
pathways in patients with eosinophilic asthma or raised serum periostin.
SUMMARY: In severe refractory asthma, both an understanding of the underlying
pathophysiologic mechanisms driving airway inflammation and the identification
of appropriate biomarkers in individual patients are critical in guiding the use
of biologics and monoclonal antibodies that target the specific pathological
processes.
DOI: 10.1097/MCP.0000000000000007
PMID: 24275927 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21445329 | 1. PLoS Biol. 2011 Mar;9(3):e1001037. doi: 10.1371/journal.pbio.1001037. Epub
2011 Mar 22.
Regarding the amazing choreography of clathrin coats.
Traub LM(1).
Author information:
(1)Department of Cell Biology and Physiology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania, United States of America. [email protected]
Comment in
PLoS Biol. 9(3):e1000604.
DOI: 10.1371/journal.pbio.1001037
PMCID: PMC3062531
PMID: 21445329 [Indexed for MEDLINE]
Conflict of interest statement: The author has declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/24122441 | 1. Hum Mol Genet. 2014 Mar 1;23(5):1163-74. doi: 10.1093/hmg/ddt510. Epub 2013
Oct 10.
Inactivation of the Carney complex gene 1 (PRKAR1A) alters spatiotemporal
regulation of cAMP and cAMP-dependent protein kinase: a study using genetically
encoded FRET-based reporters.
Cazabat L(1), Ragazzon B, Varin A, Potier-Cartereau M, Vandier C, Vezzosi D,
Risk-Rabin M, Guellich A, Schittl J, Lechêne P, Richter W, Nikolaev VO, Zhang J,
Bertherat J, Vandecasteele G.
Author information:
(1)INSERM U1016, Paris F-75014, France.
Carney complex (CNC) is a hereditary disease associating cardiac myxoma, spotty
skin pigmentation and endocrine overactivity. CNC is caused by inactivating
mutations in the PRKAR1A gene encoding PKA type I alpha regulatory subunit
(RIα). Although PKA activity is enhanced in CNC, the mechanisms linking PKA
dysregulation to endocrine tumorigenesis are poorly understood. In this study,
we used Förster resonance energy transfer (FRET)-based sensors for cAMP and PKA
activity to define the role of RIα in the spatiotemporal organization of the
cAMP/PKA pathway. RIα knockdown in HEK293 cells increased basal as well as
forskolin or prostaglandin E1 (PGE1)-stimulated total cellular PKA activity as
reported by western blots of endogenous PKA targets and the FRET-based global
PKA activity reporter, AKAR3. Using variants of AKAR3 targeted to subcellular
compartments, we identified similar increases in the response to PGE1 in the
cytoplasm and at the outer mitochondrial membrane. In contrast, at the plasma
membrane, the response to PGE1 was decreased along with an increase in basal
FRET ratio. These results were confirmed by western blot analysis of basal and
PGE1-induced phosphorylation of membrane-associated vasodilator-stimulated
phosphoprotein. Similar differences were observed between the cytoplasm and the
plasma membrane in human adrenal cells carrying a RIα inactivating mutation. RIα
inactivation also increased cAMP in the cytoplasm, at the outer mitochondrial
membrane and at the plasma membrane, as reported by targeted versions of the
cAMP indicator Epac1-camps. These results show that RIα inactivation leads to
multiple, compartment-specific alterations of the cAMP/PKA pathway revealing new
aspects of signaling dysregulation in tumorigenesis.
DOI: 10.1093/hmg/ddt510
PMCID: PMC3919008
PMID: 24122441 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23326372 | 1. PLoS One. 2013;8(1):e52989. doi: 10.1371/journal.pone.0052989. Epub 2013 Jan
9.
Mitochondrial telomerase protects cancer cells from nuclear DNA damage and
apoptosis.
Singhapol C(1), Pal D, Czapiewski R, Porika M, Nelson G, Saretzki GC.
Author information:
(1)Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle
University, Newcastle upon Tyne, United Kingdom.
Most cancer cells express high levels of telomerase and proliferate
indefinitely. In addition to its telomere maintenance function, telomerase also
has a pro-survival function resulting in an increased resistance against DNA
damage and decreased apoptosis induction. However, the molecular mechanisms for
this protective function remain elusive and it is unclear whether it is
connected to telomere maintenance or is rather a non-telomeric function of the
telomerase protein, TERT. It was shown recently that the protein subunit of
telomerase can shuttle from the nucleus to the mitochondria upon oxidative
stress where it protects mitochondrial function and decreases intracellular
oxidative stress. Here we show that endogenous telomerase (TERT protein)
shuttles from the nucleus into mitochondria upon oxidative stress in cancer
cells and analyzed the nuclear exclusion patterns of endogenous telomerase after
treatment with hydrogen peroxide in different cell lines. Cell populations
excluded TERT from the nucleus upon oxidative stress in a heterogeneous fashion.
We found a significant correlation between nuclear localization of telomerase
and high DNA damage, while cells which excluded telomerase from the nucleus
displayed no or very low DNA damage. We modeled nuclear and mitochondrial
telomerase using organelle specific localization vectors and confirmed that
mitochondrial localization of telomerase protects the nucleus from inflicted DNA
damage and apoptosis while, in contrast, nuclear localization of telomerase
correlated with higher amounts of DNA damage and apoptosis. It is known that
nuclear DNA damage can be caused by mitochondrially generated reactive oxygen
species (ROS). We demonstrate here that mitochondrial localization of telomerase
specifically prevents nuclear DNA damage by decreasing levels of mitochondrial
ROS. We suggest that this decrease of oxidative stress might be a possible cause
for high stress resistance of cancer cells and could be especially important for
cancer stem cells.
DOI: 10.1371/journal.pone.0052989
PMCID: PMC3541395
PMID: 23326372 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Gabriele Saretzki is a PLOS
ONE editor and Editorial Board member. 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/21549308 | 1. Mol Cell. 2011 May 6;42(3):297-307. doi: 10.1016/j.molcel.2011.03.020.
Processive and distributive extension of human telomeres by telomerase under
homeostatic and nonequilibrium conditions.
Zhao Y(1), Abreu E, Kim J, Stadler G, Eskiocak U, Terns MP, Terns RM, Shay JW,
Wright WE.
Author information:
(1)Department of Cell Biology, University of Texas, Southwestern Medical Center,
Dallas, TX 75390, USA.
Specific information about how telomerase acts in vivo is necessary for
understanding telomere dynamics in human tumor cells. Our results imply that,
under homeostatic telomere length-maintenance conditions, only one molecule of
telomerase acts at each telomere during every cell division and processively
adds ∼60 nt to each end. In contrast, multiple molecules of telomerase act at
each telomere when telomeres are elongating (nonequilibrium conditions).
Telomerase extension is less processive during the first few weeks following the
reversal of long-term treatment with the telomerase inhibitor Imetelstat
(GRN163L), a time when Cajal bodies fail to deliver telomerase RNA to telomeres.
This result implies that processing of telomerase by Cajal bodies may affect its
processivity. Overexpressed telomerase is also less processive than the
endogenously expressed telomerase. These findings reveal two major distinct
extension modes adopted by telomerase in vivo.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2011.03.020
PMCID: PMC3108241
PMID: 21549308 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20824134 | 1. PLoS One. 2010 Sep 1;5(9):e12487. doi: 10.1371/journal.pone.0012487.
Telomerase inhibition targets clonogenic multiple myeloma cells through telomere
length-dependent and independent mechanisms.
Brennan SK(1), Wang Q, Tressler R, Harley C, Go N, Bassett E, Huff CA, Jones RJ,
Matsui W.
Author information:
(1)Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The
Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
of America.
BACKGROUND: Plasma cells constitute the majority of tumor cells in multiple
myeloma (MM) but lack the potential for sustained clonogenic growth. In
contrast, clonotypic B cells can engraft and recapitulate disease in
immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC).
These tumor initiating B cells also share functional features with normal stem
cells such as drug resistance and self-renewal potential. Therefore, the
cellular processes that regulate normal stem cells may serve as therapeutic
targets in MM. Telomerase activity is required for the maintenance of normal
adult stem cells, and we examined the activity of the telomerase inhibitor
imetelstat against MM CSC. Moreover, we carried out both long and short-term
inhibition studies to examine telomere length-dependent and independent
activities.
METHODOLOGY/PRINCIPAL FINDINGS: Human MM CSC were isolated from cell lines and
primary clinical specimens and treated with imetelstat, a specific inhibitor of
the reverse transcriptase activity of telomerase. Two weeks of exposure to
imetelstat resulted in a significant reduction in telomere length and the
inhibition of clonogenic MM growth both in vitro and in vivo. In addition to
these relatively long-term effects, 72 hours of imetelstat treatment inhibited
clonogenic growth that was associated with MM CSC differentiation based on
expression of the plasma cell antigen CD138 and the stem cell marker aldehyde
dehydrogenase. Short-term treatment of MM CSC also decreased the expression of
genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1) as
revealed by quantitative real-time PCR.
CONCLUSIONS: Telomerase activity regulates the clonogenic growth of MM CSC.
Moreover, reductions in MM growth following both long and short-term telomerase
inhibition suggest that it impacts CSC through telomere length-dependent and
independent mechanisms.
DOI: 10.1371/journal.pone.0012487
PMCID: PMC2931698
PMID: 20824134 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: R.T., C.H., N.G., and E.B.
are employees of Geron. W.M. received research funding from Geron. 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/23516479 | 1. PLoS One. 2013;8(3):e58423. doi: 10.1371/journal.pone.0058423. Epub 2013 Mar
14.
A novel telomerase activator suppresses lung damage in a murine model of
idiopathic pulmonary fibrosis.
Le Saux CJ(1), Davy P, Brampton C, Ahuja SS, Fauce S, Shivshankar P, Nguyen H,
Ramaseshan M, Tressler R, Pirot Z, Harley CB, Allsopp R.
Author information:
(1)University of Texas Health Science Center at San Antonio, San Antonio, Texas,
USA.
The emergence of diseases associated with telomere dysfunction, including AIDS,
aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase
activators. We report identification of a new small molecule activator, GRN510,
with activity ex vivo and in vivo. Using a novel mouse model, we tested the
potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous
mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both
in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo,
respectively. Telomerase activation was countered by co-treatment with
Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of
bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of
fibrosis and accumulation of senescent cells in the lung via a mechanism
dependent upon telomerase activation. Treatment of small airway epithelial cells
(SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating
and replicative lifespan promoting effects only in the SAEC, suggesting that the
mechanism accounting for the protective effects of GRN510 against induced lung
fibrosis involves specific types of lung cells. Together, these results support
the use of small molecule activators of telomerase in therapies to treat
idiopathic pulmonary fibrosis.
DOI: 10.1371/journal.pone.0058423
PMCID: PMC3597721
PMID: 23516479 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have read the
journal's policy and have the following conflict: Authors CBH, ZP, RT, SF and MR
own stock in Geron Corporation, a company that is developing GRN510 as a
potential drug. In addition, ZP and MR are affiliated with Geron Corp, CBH is
affiliated with Telome-Health, SF is affiliated with Beckman-Coulter, and RT is
affiliated with Cellerant. None of these affiliations alter the authors'
adherence to all the PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/23526891 | 1. PLoS Comput Biol. 2013;9(3):e1002968. doi: 10.1371/journal.pcbi.1002968. Epub
2013 Mar 14.
RFECS: a random-forest based algorithm for enhancer identification from
chromatin state.
Rajagopal N(1), Xie W, Li Y, Wagner U, Wang W, Stamatoyannopoulos J, Ernst J,
Kellis M, Ren B.
Author information:
(1)Ludwig Institute for Cancer Research, University of California at San Diego,
La Jolla, CA, USA.
Transcriptional enhancers play critical roles in regulation of gene expression,
but their identification in the eukaryotic genome has been challenging.
Recently, it was shown that enhancers in the mammalian genome are associated
with characteristic histone modification patterns, which have been increasingly
exploited for enhancer identification. However, only a limited number of cell
types or chromatin marks have previously been investigated for this purpose,
leaving the question unanswered whether there exists an optimal set of histone
modifications for enhancer prediction in different cell types. Here, we address
this issue by exploring genome-wide profiles of 24 histone modifications in two
distinct human cell types, embryonic stem cells and lung fibroblasts. We
developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer
identification from Chromatin States) to integrate histone modification profiles
for identification of enhancers, and used it to identify enhancers in a number
of cell-types. We show that RFECS not only leads to more accurate and precise
prediction of enhancers than previous methods, but also helps identify the most
informative and robust set of three chromatin marks for enhancer prediction.
DOI: 10.1371/journal.pcbi.1002968
PMCID: PMC3597546
PMID: 23526891 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/25645542 | 1. Hautarzt. 2015 Feb;66(2):108-13. doi: 10.1007/s00105-014-3575-8.
[Status quo and prospects for systemic therapy of atopic dermatitis. Biologics
ante portas].
[Article in German]
Biedermann T(1), Werfel T.
Author information:
(1)Klinik und Poliklinik für Dermatologie und Allergologie, Biedersteinerstraße
29, 80802, München, Deutschland.
Currently the only approved drug available for the systemic therapy of atopic
dermatitis is cyclosporine; however, based on current data from published
studies, azathioprine, methotrexate, and mycophenolate mofetil or mycophenolic
acid can be administered off-label. Some biologics on the market that have been
approved for other indications (ustekinumab, rituximab, tocilizumab) have been
successfully used in a few patients with atopic dermatitis. The world's first
prospective controlled studies with the biologic human anti-IL4R antibody
dupilumab for the indication "atopic dermatitis" were published in 2014. These
motivated (1) to extend the studies to dupilumab and (2) to clinically test
antagonization of other target molecules of TH2 polarized, atopic inflammation,
e.g., IL-13, IL-31, IL-22, TSLP, and CRTH2. A number of clinical trials are
currently recruiting in this area and will provide interesting new insights for
future therapeutic approaches in atopic dermatitis.
DOI: 10.1007/s00105-014-3575-8
PMID: 25645542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23688323 | 1. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub
2013 May 21.
Dupilumab in persistent asthma with elevated eosinophil levels.
Wenzel S(1), Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L,
Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N,
Yancopoulos GD, Graham N, Pirozzi G.
Author information:
(1)Division of Pulmonary Allergy and Critical Care Medicine, University of
Pittsburgh, Pittsburgh, PA, USA. [email protected]
Comment in
N Engl J Med. 2013 Jun 27;368(26):2511-3. doi: 10.1056/NEJMe1305426.
N Engl J Med. 2013 Sep 26;369(13):1276. doi: 10.1056/NEJMc1309809.
N Engl J Med. 2013 Sep 26;369(13):1275. doi: 10.1056/NEJMc1309809.
N Engl J Med. 2013 Sep 26;369(13):1275-6. doi: 10.1056/NEJMc1309809.
BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the
efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal
antibody to the alpha subunit of the interleukin-4 receptor, in patients with
persistent, moderate-to-severe asthma and elevated eosinophil levels.
METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a
blood eosinophil count of at least 300 cells per microliter or a sputum
eosinophil level of at least 3% who used medium-dose to high-dose inhaled
glucocorticoids plus long-acting beta-agonists (LABAs). We administered
dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were
instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled
glucocorticoids during weeks 6 through 9. Patients received the study drug for
12 weeks or until a protocol-defined asthma exacerbation occurred. The primary
end point was the occurrence of an asthma exacerbation; secondary end points
included a range of measures of asthma control. Effects on various type 2 helper
T-cell (Th2)-associated biomarkers and safety and tolerability were also
evaluated.
RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52
patients were assigned to the placebo group. Baseline characteristics were
similar in the two groups. Three patients had an asthma exacerbation with
dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction
with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28;
P<0.001). Significant improvements were observed for most measures of lung
function and asthma control. Dupilumab reduced biomarkers associated with
Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and
headache occurred more frequently with dupilumab than with placebo.
CONCLUSIONS: In patients with persistent, moderate-to-severe asthma and elevated
eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy,
as compared with placebo, was associated with fewer asthma exacerbations when
LABAs and inhaled glucocorticoids were withdrawn, with improved lung function
and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and
Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
DOI: 10.1056/NEJMoa1304048
PMID: 23688323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24037088 | 1. Cell Death Differ. 2013 Dec;20(12):1675-87. doi: 10.1038/cdd.2013.119. Epub
2013 Sep 13.
HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts.
Ferdin J(1), Nishida N, Wu X, Nicoloso MS, Shah MY, Devlin C, Ling H, Shimizu M,
Kumar K, Cortez MA, Ferracin M, Bi Y, Yang D, Czerniak B, Zhang W, Schmittgen
TD, Voorhoeve MP, Reginato MJ, Negrini M, Davuluri RV, Kunej T, Ivan M, Calin
GA.
Author information:
(1)1] Department of Experimental Therapeutics, The Center for RNA Interference
and Non-Coding RNAs, MD Anderson Cancer Center, The University of Texas, So
Campus Research Building 3, 1881 East Road, Houston, TX 77030, USA [2] Chair of
Genetics, Animal Biotechnology and Immunology, Department of Animal Science,
Biotechnical Faculty, University of Ljubljana, Groblje 3 1230, Domzale,
Slovenia.
Recent data have linked hypoxia, a classic feature of the tumor
microenvironment, to the function of specific microRNAs (miRNAs); however,
whether hypoxia affects other types of noncoding transcripts is currently
unknown. Starting from a genome-wide expression profiling, we demonstrate for
the first time a functional link between oxygen deprivation and the modulation
of long noncoding transcripts from ultraconserved regions, termed
transcribed-ultraconserved regions (T-UCRs). Interestingly, several
hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding
ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical
samples from colon cancer patients. We show that these T-UCRs are predominantly
nuclear and that the hypoxia-inducible factor (HIF) is at least partly
responsible for the induction of several members of this group. One specific
HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host
protein-coding gene, O-linked N-acetylglucosamine transferase, which is
overexpressed in epithelial cancer types. Consistent with the hypothesis that
T-UCRs have important function in tumor formation, HINCUT-1 supports cell
proliferation specifically under hypoxic conditions and may be critical for
optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data
gives a first glimpse of a novel functional hypoxic network comprising
protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.
DOI: 10.1038/cdd.2013.119
PMCID: PMC3824588
PMID: 24037088 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19908230 | 1. Int J Cancer. 2010 Jul 15;127(2):321-31. doi: 10.1002/ijc.25043.
The effects of telomerase inhibition on prostate tumor-initiating cells.
Marian CO(1), Wright WE, Shay JW.
Author information:
(1)Department of Cell Biology, University of Texas Southwestern Medical Center,
Dallas, TX, USA.
Prostate cancer is the most common malignancy in men, and patients with
metastatic disease have poor outcome even with the most advanced therapeutic
approaches. Most cancer therapies target the bulk tumor cells, but may leave
intact a small population of tumor-initiating cells (TICs), which are believed
to be responsible for the subsequent relapse and metastasis. Using specific
surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye
exclusion, and holoclone formation, we isolated TICs from a panel of prostate
cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have
significant telomerase activity which is inhibited by imetelstat sodium
(GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical
trials for several hematological and solid tumor malignancies. Prostate TICs
telomeres were of similar average length to the telomeres of the main population
of cells and significant telomere shortening was detected in prostate TICs as a
result of imetelstat treatment. These findings suggest that telomerase
inhibition therapy may be able to efficiently target the prostate TICs in
addition to the bulk tumor cells, providing new opportunities for combination
therapies.
DOI: 10.1002/ijc.25043
PMID: 19908230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22870217 | 1. PLoS One. 2012;7(8):e41401. doi: 10.1371/journal.pone.0041401. Epub 2012 Aug
3.
Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in
osteosarcoma.
Saini V(1), Hose CD, Monks A, Nagashima K, Han B, Newton DL, Millione A, Shah J,
Hollingshead MG, Hite KM, Burkett MW, Delosh RM, Silvers TE, Scudiero DA,
Shoemaker RH.
Author information:
(1)Screening Technologies Branch, Developmental Therapeutics Program, Division
of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick,
Frederick, Maryland, United States of America.
Erratum in
PLoS One. 2012;7(11).
doi:10.1371/annotation/8c74aaee-897d-4682-b62d-d95a3506c210.
Recently, there has been renewed interest in the role of tumor stem cells (TSCs)
in tumorigenesis, chemoresistance, and relapse of malignant tumors including
osteosarcoma. The potential exists to improve osteosarcoma treatment through
characterization of TSCs and identification of therapeutic targets. Using
transcriptome, proteome, immunophenotyping for cell-surface markers, and
bioinformatic analyses, heterogeneous expression of previously reported TSC or
osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and
aldehyde dehydrogenase, among others, was observed in vitro. However,
consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression
in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed.
In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma
cultures was identified. ABCA5 was identified as a putative biomarker of TSCs
and/or osteosarcoma. Lastly, in a high-throughput screen we identified
epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase
(3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate;
RHPS4)-targeted therapeutic agents as candidates for TSC ablation in
osteosarcoma.
DOI: 10.1371/journal.pone.0041401
PMCID: PMC3411700
PMID: 22870217 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. There are no financial, personal, or
professional interests that could be construed to have influenced the paper.
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/20802525 | 1. Oncogene. 2010 Dec 2;29(48):6390-401. doi: 10.1038/onc.2010.361. Epub 2010 Aug
30.
CpG island hypermethylation-associated silencing of non-coding RNAs transcribed
from ultraconserved regions in human cancer.
Lujambio A(1), Portela A, Liz J, Melo SA, Rossi S, Spizzo R, Croce CM, Calin GA,
Esteller M.
Author information:
(1)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute (IDIBELL), 08907L'Hospitalet, Barcelona, Spain.
Erratum in
Oncogene. 2019 Jan;38(5):765-766. doi: 10.1038/s41388-018-0560-1.
Although only 1.5% of the human genome appears to code for proteins, much effort
in cancer research has been devoted to this minimal fraction of our DNA.
However, the last few years have witnessed the realization that a large class of
non-coding RNAs (ncRNAs), named microRNAs, contribute to cancer development and
progression by acting as oncogenes or tumor suppressor genes. Recent studies
have also shown that epigenetic silencing of microRNAs with tumor suppressor
features by CpG island hypermethylation is a common hallmark of human tumors.
Thus, we wondered whether there were other ncRNAs undergoing aberrant DNA
methylation-associated silencing in transformed cells. We focused on the
transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are
absolutely conserved between orthologous regions of the human, rat and mouse
genomes and that are located in both intra- and intergenic regions. We used a
pharmacological and genomic approach to reveal the possible existence of an
aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a
DNA-demethylating agent followed by hybridization to an expression microarray
containing these sequences. We observed that DNA hypomethylation induces release
of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon
drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG
island hypermethylation-associated silencing in cancer cells compared with
normal tissues. The analysis of a large set of primary human tumors (n=283)
demonstrated that hypermethylation of the described T-UCR CpG islands was a
common event among the various tumor types. Our finding that, in addition to
microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated
inactivation in transformed cells supports a model in which epigenetic and
genetic alterations in coding and non-coding sequences cooperate in human
tumorigenesis.
DOI: 10.1038/onc.2010.361
PMCID: PMC3007676
PMID: 20802525 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22617881 | 1. RNA Biol. 2012 Jun;9(6):881-90. doi: 10.4161/rna.19353. Epub 2012 May 23.
CpG island hypermethylation-associated silencing of small nucleolar RNAs in
human cancer.
Ferreira HJ(1), Heyn H, Moutinho C, Esteller M.
Author information:
(1)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute (IDIBELL), Barcelona, Catalonia, Spain.
Much effort in cancer research has focused on the tiny part of our genome that
codes for mRNA. However, it has recently been recognized that microRNAs also
contribute decisively to tumorigenesis. Studies have also shown that epigenetic
silencing by CpG island hypermethylation of microRNAs with tumor suppressor
activities is a common feature of human cancer. The importance of other classes
of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed
ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also
gaining recognition. Thus, we wondered whether there were other ncRNAs
undergoing CpG island hypermethylation-associated inactivation in cancer cells.
We focused on the small nucleolar RNAs (snoRNAs), a subset of ncRNA with a wide
variety of cellular functions, such as chemical modification of RNA, pre-RNA
processing and control of alternative splicing. By data mining snoRNA databases
and the scientific literature, we selected 49 snoRNAs that had a CpG island
within ≤ 2 Kb or that were processed from a host gene with a 5'-CpG island.
Bisulfite genomic sequencing of multiple clones in normal colon mucosa and the
colorectal cancer cell line HCT-116 showed that 46 snoRNAs were equally
methylated in the two samples: completely unmethylated (n = 26) or fully
methylated (n = 20). Most interestingly, the host gene-associated 5'-CpG islands
of the snoRNAs SNORD123, U70C and ACA59B were hypermethylated in the cancer
cells but not in the corresponding normal tissue. CpG island hypermethylation
was associated with the transcriptional silencing of the respective snoRNAs.
Results of a DNA methylation microarray platform in a comprehensive collection
of normal tissues, cancer cell lines and primary malignancies demonstrated that
the observed hypermethylation of snoRNAs was a common feature of various tumor
types, particularly in leukemias. Overall, our findings indicate the existence
of a new subclass of ncRNAs, snoRNAs, that are targeted by epigenetic
inactivation in human cancer.
DOI: 10.4161/rna.19353
PMCID: PMC3495749
PMID: 22617881 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21298224 | 1. ScientificWorldJournal. 2011 Feb 3;11:340-52. doi: 10.1100/tsw.2011.35.
The transcribed-ultraconserved regions: a novel class of long noncoding RNAs
involved in cancer susceptibility.
Scaruffi P(1).
Author information:
(1)Center of Physiopathology of Human Reproduction, Department of Obstetrics and
Gynecology, San Martino Hospital, Genoa, Italy. [email protected]
During recent years, novel approaches and new technologies have revealed a
startling level of complexity of higher eukaryotes' transcriptome. A large
proportion of the transcriptional output is represented by protein noncoding
RNAs (ncRNAs) that arise from the "dark matter" of the genome. Focus on such
sequences has revealed numerous RNA subtypes with several functions in RNA
processing and gene expression regulation, and deep sequencing studies imply
that many remain to be discovered. This review gives a picture of the state of
the art of a novel class of long ncRNA known as transcribed-ultraconserved
regions (T-UCRs). Most recent studies show that they are significantly altered
in adult chronic lymphocytic leukemias, carcinomas, and pediatric
neuroblastomas, leading to the hypothesis that UCRs may play a role in
tumorigenesis and promising innovative future T-UCR-based therapeutic
approaches.
DOI: 10.1100/tsw.2011.35
PMCID: PMC5720018
PMID: 21298224 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25214796 | 1. J Asthma Allergy. 2014 Sep 4;7:123-30. doi: 10.2147/JAA.S52387. eCollection
2014.
Dupilumab: a novel treatment for asthma.
Vatrella A(1), Fabozzi I(1), Calabrese C(2), Maselli R(3), Pelaia G(3).
Author information:
(1)Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
(2)Department of Cardiothoracic and Respiratory Sciences, Second University of
Naples, Naples, Italy.
(3)Department of Medical and Surgical Sciences, University Magna Græcia,
Catanzaro, Italy.
Simultaneously with the steady progress towards a better knowledge of the
pathobiology of asthma, the potential usefulness of anticytokine therapies is
emerging as one of the key concepts in the newly developing treatments of this
widespread airway disease. In particular, given the key role played by
interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects
of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial
hyperresponsiveness, these pleiotropic cytokines are now considered as suitable
therapeutic targets. Among the recently developed antiasthma biologic drugs, the
monoclonal antibody dupilumab is very promising because of its ability to
inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab
prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A
recent trial showed that in patients with difficult-to-control asthma, dupilumab
can markedly decrease asthma exacerbations and improve respiratory symptoms and
lung function; these effects were paralleled by significant reductions in
T-helper 2-associated inflammatory biomarkers. However, further larger and
longer trials are required to extend and validate these preliminary results, and
also to carefully study the safety and tolerability profile of dupilumab.
DOI: 10.2147/JAA.S52387
PMCID: PMC4159398
PMID: 25214796 |
http://www.ncbi.nlm.nih.gov/pubmed/17042739 | 1. J Bone Miner Res. 2007 Jan;22(1):7-18. doi: 10.1359/jbmr.061012.
Craniosynostosis-associated gene nell-1 is regulated by runx2.
Truong T(1), Zhang X, Pathmanathan D, Soo C, Ting K.
Author information:
(1)Dental of Craniofacial Research Institute, University of California, Los
Angeles, CA 90095, USA.
We studied the transcriptional regulation of NELL-1, a craniosynostosis-related
gene. We identitifed three OSE2 elements in the NELL-1 promoter that are
directly bound and transactivated by Runx2. Forced expression of Runx2 induces
NELL-1 expression in rat calvarial cells.
INTRODUCTION: We previously reported the upregulation of NELL-1 in human
craniosynostosis and the overexpression of Nell-1 in transgenic animals that
induced premature suture closure associated with increased osteoblast
differentiation. To study the transcriptional regulation of NELL-1, we analyzed
the 5' flanking region of the human NELL-1 gene. We identified three osteoblast
specific binding elements 2 (OSE2) sites (A, B, and C) within 2.2 kb upstream of
the transcription start site and further studied the functionality of these
sites.
MATERIALS AND METHODS: An area of 2.2 kb and a truncated 325 bp, which lacked
the three OSE sites, were cloned into a luciferase reporter gene, and
co-transfected with Runx2 expression plasmid. The three OSE2 sites were
individually mutated and co-transfected with Runx2 expression plasmid into Saos2
cells. Gel shifts and supershifts with Runx2 antibodies were used to determine
specific binding to OSE2 sites. CHIP assays were used to study in vivo binding
of Runx2 to the Nell-1 promoter. Runx2 expression plasmid was transfected into
wildtype and Runx2(-/-) calvarial cells. Nell-1, osteocalcin, and Runx2
expression levels were measured using RT-PCR.
RESULTS: Addition of Runx2 dose-dependently increased the luciferase activity in
the human NELL-1 promoter-luciferase p2213. The p325 truncated NELL-1 construct
showed significantly lower basal level of activity. Nuclear extract from Saos2
cells formed complexes with site A, B, and C probes and were supershifted with
Runx2 antibody. Mutation of sites A, B, and C significantly decreased basal
promoter activity. Furthermore, mutation of sites B and C had a blunted response
to Runx2, whereas mutation of site A had a lesser effect. Runx2 bound to NELL-1
promoter in vivo. Transfection of Runx2 in rat osteoblasts upregulated Nell-1
and Ocn expression, and in Runx2 null calvarial cells, both Nell-1 and Ocn
expression were rescued.
CONCLUSIONS: Runx2 directly binds to the OSE2 elements and transactivates the
human NELL-1 promoter. These results suggest that Nell-1 is likely a downstream
target of Runx2. These findings may also extend our understanding of the
molecular mechanisms governing the pathogenesis of craniosynostosis.
DOI: 10.1359/jbmr.061012
PMID: 17042739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24247010 | 1. Epigenetics. 2014 Jan;9(1):113-8. doi: 10.4161/epi.27237. Epub 2013 Nov 18.
Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.
Ferreira HJ(1), Heyn H(2), Garcia del Muro X(3), Vidal A(4), Larriba S(5), Muñoz
C(6), Villanueva A(6), Esteller M(7).
Author information:
(1)Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research
Institute (IDIBELL); Barcelona, Spain; Programme in Experimental Biology and
Biomedicine; Centre for Neurosciences and Cell Biology; University of Coimbra;
Coimbra, Portugal.
(2)Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research
Institute (IDIBELL); Barcelona, Spain.
(3)Medical Oncology Department; Catalan Institute of Oncology; Bellvitge
Biomedical Research Institute (IDIBELL); Barcelona, Spain.
(4)Pathology Department; University Hospital Bellvitge; Bellvitge Biomedical
Research Institute (IDIBEL); Barcelona, Spain.
(5)Human Molecular Genetics Group; Bellvitge Biomedical Research Institute
(IDIBELL); Barcelona, Spain.
(6)Translational Research Laboratory; Catalan Institute of Oncology; Bellvitge
Biomedical Research Institute (IDIBELL); Barcelona, Spain.
(7)Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research
Institute (IDIBELL); Barcelona, Spain; Department of Physiological Sciences II;
School of Medicine; University of Barcelona; Barcelona, Spain; Institucio
Catalana de Recerca i Estudis Avançats (ICREA); Barcelona, Spain.
Although most cancer research has focused in mRNA, non-coding RNAs are also an
essential player in tumorigenesis. In addition to the well-recognized microRNAs,
recent studies have also shown that epigenetic silencing by CpG island
hypermethylation of other classes of non-coding RNAs, such as transcribed
ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in
human neoplasia. Herein we have studied the putative existence of epigenetic
aberrations in the activity of PIWI proteins, an Argonaute family protein
subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular
cancer, as the PIWI/piRNA pathway plays a critical role in male germline
development. We have observed the existence of promoter CpG island
hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in
primary seminoma and non-seminoma testicular tumors, in addition to testicular
germ cell tumor cell lines. Most importantly, these epigenetic lesions occur in
a context of piRNA downregulation and loss of DNA methylation of the LINE-1
repetitive sequences, one of the target genomic loci where the PIWI/piRNA
machinery acts as a caretaker in non-transformed cells.
DOI: 10.4161/epi.27237
PMCID: PMC3928173
PMID: 24247010 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25006719 | 1. N Engl J Med. 2014 Jul 10;371(2):130-9. doi: 10.1056/NEJMoa1314768.
Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.
Beck LA(1), Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, Ming JE, Ren
H, Kao R, Simpson E, Ardeleanu M, Weinstein SP, Pirozzi G, Guttman-Yassky E,
Suárez-Fariñas M, Hager MD, Stahl N, Yancopoulos GD, Radin AR.
Author information:
(1)From the Department of Dermatology, University of Rochester Medical Center,
Rochester (L.A.B.), Regeneron Pharmaceuticals, Tarrytown (J.D.H., N.M.G., H.R.,
R.K., M.A., S.P.W., M.D.H., N.S., G.D.Y., A.R.R.), the Department of Dermatology
and the Immunology Institute, Icahn School of Medicine at Mount Sinai (E.G.-Y.),
the Laboratory for Investigative Dermatology (E.G.-Y., M.S.-F.) and the Center
for Clinical and Translational Science (M.S.-F.), Rockefeller University, New
York - all in New York; the Department of Dermatology, Allergology, and
Venereology, Universität zu Lübeck, Lübeck (D.T.), and the Department of
Dermatology and Allergology, University of Bonn, Bonn (T.B.) - both in Germany;
Sanofi, Bridgewater, NJ (R.R., J.E.M., G.P.); and the Department of Dermatology,
Oregon Health and Science University, Portland (E.S.).
BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks
interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and
elevated eosinophil levels. The blockade by dupilumab of these key drivers of
type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of
related diseases, including atopic dermatitis.
METHODS: We performed randomized, double-blind, placebo-controlled trials
involving adults who had moderate-to-severe atopic dermatitis despite treatment
with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated
as monotherapy in two 4-week trials and in one 12-week trial and in combination
with topical glucocorticoids in another 4-week study. End points included the
Eczema Area and Severity Index (EASI) score, the investigator's global
assessment score, pruritus, safety assessments, serum biomarker levels, and
disease transcriptome.
RESULTS: In the 4-week monotherapy studies, dupilumab resulted in rapid and
dose-dependent improvements in clinical indexes, biomarker levels, and the
transcriptome. The results of the 12-week study of dupilumab monotherapy
reproduced and extended the 4-week findings: 85% of patients in the dupilumab
group, as compared with 35% of those in the placebo group, had a 50% reduction
in the EASI score (EASI-50, with higher scores in the EASI indicating greater
severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as
compared with 7% in the placebo group, had a score of 0 to 1 (indicating
clearing or near-clearing of skin lesions) on the investigator's global
assessment (P<0.001); and pruritus scores decreased (indicating a reduction in
itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group
(P<0.001). In the combination study, 100% of the patients in the dupilumab
group, as compared with 50% of those who received topical glucocorticoids with
placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact
that patients who received dupilumab plus glucocorticoids used less than half
the amount of topical glucocorticoids used by those who received placebo plus
the topical medication (P=0.16). Adverse events, such as skin infection,
occurred more frequently with placebo; nasopharyngitis and headache were the
most frequent adverse events with dupilumab.
CONCLUSIONS: Patients treated with dupilumab had marked and rapid improvement in
all the evaluated measures of atopic dermatitis disease activity. Side-effect
profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and
Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and
NCT01548404.).
DOI: 10.1056/NEJMoa1314768
PMID: 25006719 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9585042 | 1. Clin Radiol. 1998 Apr;53(4):268-73. doi: 10.1016/s0009-9260(98)80125-6.
Radiological malformations of the ear in Pendred syndrome.
Phelps PD(1), Coffey RA, Trembath RC, Luxon LM, Grossman AB, Britton KE,
Kendall-Taylor P, Graham JM, Cadge BC, Stephens SG, Pembrey ME, Reardon W.
Author information:
(1)Royal National Throat Nose and Ear Hospital, London, UK.
Pendred syndrome comprises the association of severe congenital sensorineural
deafness with thyroid pathology. Although it is the commonest form of syndromic
hearing loss, the primary genetic defect remains unknown. The variable clinical
presentation allied to the difficulty in securing the diagnosis have resulted in
relatively poor documentation of the radiological features of this syndrome. We
now present data on 40 patients, all complying with strict diagnostic criteria
for the disorder, and describe our experience of the prevalence of specific
malformations of the inner ear as well as comparing the relative merits of
computed tomography (CT) and magnetic resonance imaging (MRI) in the
investigation of this inherited condition. Deficiency of the interscalar septum
in the distal coils of the cochlea (Mondini deformity) was found to be a common
but probably not a constant feature of Pendred syndrome. However, enlargement of
the endolymphatic sac and duct in association with a large vestibular aqueduct
was present in all 20 patients examined by MRI. We conclude that thin section
high resolution MRI on a T2 protocol in the axial and sagittal planes is the
imaging investigation of choice.
DOI: 10.1016/s0009-9260(98)80125-6
PMID: 9585042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22328099 | 1. Oncology. 2012;82(2):114-8. doi: 10.1159/000336479. Epub 2012 Feb 11.
Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are
altered in colorectal cancer.
Sana J(1), Hankeova S, Svoboda M, Kiss I, Vyzula R, Slaby O.
Author information:
(1)Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute,
Brno, Czech Republic.
OBJECTIVES: The development of colorectal cancer (CRC) is characterized by
multiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a
subset of 481 sequences longer than 200 bp, which are absolutely conserved
between orthologous regions of human, rat and mouse genomes, and are actively
transcribed. It has recently been proven in cancer systems that differentially
expressed T-UCRs could alter the functional characteristics of malignant cells.
Genome-wide profiling revealed that T-UCRs have distinct signatures in human
leukemia and carcinoma.
METHODS: In our study, we examined the expression levels of uc.43, uc.73,
uc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal
carcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR.
T-UCR expression levels were also correlated with commonly used
clinicopathological features of CRC.
RESULTS: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were
significantly decreased in CRC tissue, and uc.73 indicated a positive
correlation with overall survival (p = 0.0315). The lower expression of uc.388
was associated with the distal location of CRC (p = 0.0183), but no correlation
of any evaluated T-UCR with clinical stage, grade and tumor diameter was
observed.
CONCLUSION: Our preliminary results suggest that uc.73 and uc.388 could be
potential diagnostic and prognostic biomarkers in CRC patients.
Copyright © 2012 S. Karger AG, Basel.
DOI: 10.1159/000336479
PMID: 22328099 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18323801 | 1. Leukemia. 2008 Jun;22(6):1095-105. doi: 10.1038/leu.2008.30. Epub 2008 Mar 6.
MicroRNAs and noncoding RNAs in hematological malignancies: molecular, clinical
and therapeutic implications.
Fabbri M(1), Garzon R, Andreeff M, Kantarjian HM, Garcia-Manero G, Calin GA.
Author information:
(1)Human Cancer Genetics, Molecular Virology, Immunology and Medical Genetics,
Ohio State University, Columbus, OH, USA.
MicroRNAs (miRNAs) are a family of 19-24 nucleotide noncoding RNAs (ncRNAs) with
posttranscriptional regulatory functions. Increasing evidences from the
literature show that miRNAs play a pivotal role in human tumorigenesis. Many
studies have addressed the role of miRNAs in normal hematopoiesis, giving an
interpretative key to the aberrancies of expression observed in human
hematological malignancies. Moreover, the recent demonstration that other
ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions
(T-UCRs), are involved in human cancerogenesis, suggests that the wider family
of ncRNAs (including both miRNAs and UCGs) could contribute to the development
of the malignant phenotype. Here we review the main studies investigating the
role of miRNAs and UCRs in both normal hemopoiesis and hematological
malignancies, and identify the molecular, clinical and therapeutic implications
of these recent findings.
DOI: 10.1038/leu.2008.30
PMID: 18323801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11375792 | 1. Eur J Endocrinol. 2001 Jun;144(6):585-93. doi: 10.1530/eje.0.1440585.
Clinical and molecular analysis of three Mexican families with Pendred's
syndrome.
Gonzalez Trevino O(1), Karamanoglu Arseven O, Ceballos CJ, Vives VI, Ramirez RC,
Gomez VV, Medeiros-Neto G, Kopp P.
Author information:
(1)Department of Nuclear Medicine and Thyroid Clinic, Instituto Nacional
Nutrition S. Zubiran, Mexico City, Mexico.
BACKGROUND: The autosomal recessive Pendred's syndrome is defined by congenital
sensorineural deafness, goiter, and impaired iodide organification. It is caused
by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a
chloride/iodide transporter expressed in the thyroid, the inner ear, and the
kidney.
OBJECTIVE: To perform a detailed clinical and molecular analysis of patients
with Pendred's syndrome from four patients from three unrelated Mexican
families.
METHODS: Thyroid function tests, perchlorate test, thyroid scintigraphy,
audiometry, computer tomography and magnetic resonance imaging were performed in
all affected individuals. Haplotype analyses were performed using microsatellite
markers flanking the PDS locus, and the PDS gene was submitted to direct
sequence analysis.
RESULTS: All patients presented with sensorineural deafness, Mondini
malformations of the cochlea, an enlarged vestibular aqueduct, goiter, and a
positive perchlorate test. Two patients were hypothyroid, two individuals were
euthyroid. Sequence analysis revealed a complex homozygous deletion/insertion
mutation at the end of exon 4 in the index patient of family 1 resulting in a
premature stop codon at position 138. In family 2, the affected individuals were
compound heterozygous for a splice acceptor mutation (IVS2 -1G>A) and a 1231G>C
transversion substituting alanine 411 by proline (A411P). In family 3, the index
patient was found to be homozygous for a transversion 412G>T in exon 4 replacing
valine 138 by phenylalanine (V138F).
CONCLUSIONS: All patients included in this study presented with the classic
Pendred syndrome triad and molecular analysis revealed pendrin mutations as the
underlying cause. The identification of three novel mutations, one of them of
complex structure, expands the spectrum of mutations in the PDS gene and
emphasizes that they display marked allelic heterogeneity.
DOI: 10.1530/eje.0.1440585
PMID: 11375792 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10914960 | 1. Acta Paediatr. 2000 Jun;89(6):672-4. doi: 10.1080/080352500750043972.
A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3)
causes non-syndromic craniosynostosis.
Tsai FJ(1), Wu JY, Lee CC, Tsa CH.
Author information:
(1)Department of Pediatrics, China Medical College Hospital, Taichung, Taiwan.
[email protected]
A unique Pro250Arg mutation in fibroblast growth factor receptor 3 (FGFR3) was
recently found in patients with non-syndromic craniosynostosis. We studied 18
Taiwan Chinese patients with various types of craniosynostosis to evaluate if
this mutation is also prevalent in the Chinese population. Genomic DNA was
analysed by polymerase chain reaction based restriction analysis and direct
sequencing to identify the Pro250Arg mutation in FGFR3. Five (28%) of 18
probands were heterozygous for the Pro250Arg mutation. Only those patients with
coronal synostosis carried this mutation.
CONCLUSION: Our findings suggest that all patients with coronal synostosis
should be examined for this unique mutation.
DOI: 10.1080/080352500750043972
PMID: 10914960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25524798 | 1. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub
2014 Dec 16.
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with
letrozole versus letrozole alone as first-line treatment of oestrogen
receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a
randomised phase 2 study.
Finn RS(1), Crown JP(2), Lang I(3), Boer K(4), Bondarenko IM(5), Kulyk SO(6),
Ettl J(7), Patel R(8), Pinter T(9), Schmidt M(10), Shparyk Y(11), Thummala
AR(12), Voytko NL(13), Fowst C(14), Huang X(15), Kim ST(15), Randolph S(15),
Slamon DJ(16).
Author information:
(1)University of California Los Angeles, Los Angeles, CA, USA.
(2)Irish Cooperative Oncology Research Group, Dublin, Ireland.
(3)Orszagos Onkologiai Intezet, Budapest, Hungary.
(4)Szent Margit Korhaz, Onkologia, Budapest, Hungary.
(5)Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital 4,
Dnipropetrovsk, Ukraine.
(6)Municipal Treatment and Prophylactic Institution, Donetsk, Ukraine.
(7)Technical University of Munich, Munich, Germany.
(8)Comprehensive Blood and Cancer Center, Bakersfield, CA, USA.
(9)Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary.
(10)University Hospital Mainz, Mainz, Germany.
(11)Lviv State Oncologic Regional Treatment and Diagnostic Centre, Lviv,
Ukraine.
(12)Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
(13)Kyiv City Clinical Oncology Centre, Kyiv, Ukraine.
(14)Pfizer Oncology, Milan, Italy.
(15)Pfizer Oncology, San Diego, CA, USA.
(16)University of California Los Angeles, Los Angeles, CA, USA. Electronic
address: [email protected].
Comment in
Lancet Oncol. 2015 Jan;16(1):2-3. doi: 10.1016/S1470-2045(14)71188-X.
BACKGROUND: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of
cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of
growth-inhibitory activity in oestrogen receptor-positive breast cancer cells
and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of
palbociclib in combination with letrozole as first-line treatment of patients
with advanced, oestrogen receptor-positive, HER2-negative breast cancer.
METHODS: In this open-label, randomised phase 2 study, postmenopausal women with
advanced oestrogen receptor-positive and HER2-negative breast cancer who had not
received any systemic treatment for their advanced disease were eligible to
participate. Patients were enrolled in two separate cohorts that accrued
sequentially: in cohort 1, patients were enrolled on the basis of their
oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in
cohort 2 they were also required to have cancers with amplification of cyclin D1
(CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were
randomly assigned 1:1 via an interactive web-based randomisation system,
stratified by disease site and disease-free interval, to receive continuous oral
letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral
palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over
28-day cycles. The primary endpoint was investigator-assessed progression-free
survival in the intention-to-treat population. Accrual to cohort 2 was stopped
after an unplanned interim analysis of cohort 1 and the statistical analysis
plan for the primary endpoint was amended to a combined analysis of cohorts 1
and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual;
these are the results of the final analysis of progression-free survival. The
study is registered with the ClinicalTrials.gov, number NCT00721409.
FINDINGS: Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165
patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the
time of the final analysis for progression-free survival (median follow-up 29.6
months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9
months [25.5-31.1] for the letrozole group), 41 progression-free survival events
had occurred in the palbociclib plus letrozole group and 59 in the letrozole
group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for
the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus
letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1
(n=66), median progression-free survival was 5.7 months (2.6-10.5) for the
letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus
letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in cohort 2 (n=99),
median progression-free survival was 11.1 months (7.1-16.4) for the letrozole
group and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR
0.508, 0.303-0.853; one-sided p=0.0046). Grade 3-4 neutropenia was reported in
45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%)
of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and
fatigue in four (4%) versus one (1%). Serious adverse events that occurred in
more than one patient in the palbociclib plus letrozole group were pulmonary
embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]).
No cases of febrile neutropenia or neutropenia-related infections were reported
during the study. 11 (13%) patients in the palbociclib plus letrozole group and
two (2%) in the letrozole group discontinued the study because of adverse
events.
INTERPRETATION: The addition of palbociclib to letrozole in this phase 2 study
significantly improved progression-free survival in women with advanced
oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is
currently underway.
FUNDING: Pfizer.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(14)71159-3
PMID: 25524798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20383195 | 1. Oncogene. 2010 Jun 17;29(24):3583-92. doi: 10.1038/onc.2010.106. Epub 2010 Apr
12.
An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma
tumours.
Mestdagh P(1), Fredlund E, Pattyn F, Rihani A, Van Maerken T, Vermeulen J, Kumps
C, Menten B, De Preter K, Schramm A, Schulte J, Noguera R, Schleiermacher G,
Janoueix-Lerosey I, Laureys G, Powel R, Nittner D, Marine JC, Ringnér M,
Speleman F, Vandesompele J.
Author information:
(1)Center for Medical Genetics, Ghent University Hospital, Ghent, East-Flanders,
Belgium.
Different classes of non-coding RNAs, including microRNAs, have recently been
implicated in the process of tumourigenesis. In this study, we examined the
expression and putative functions of a novel class of non-coding RNAs known as
transcribed ultraconserved regions (T-UCRs) in neuroblastoma. Genome-wide
expression profiling revealed correlations between specific T-UCR expression
levels and important clinicogenetic parameters such as MYCN amplification
status. A functional genomics approach based on the integration of multi-level
transcriptome data was adapted to gain insights into T-UCR functions.
Assignments of T-UCRs to cellular processes such as TP53 response,
differentiation and proliferation were verified using various cellular model
systems. For the first time, our results define a T-UCR expression landscape in
neuroblastoma and suggest widespread T-UCR involvement in diverse cellular
processes that are deregulated in the process of tumourigenesis.
DOI: 10.1038/onc.2010.106
PMID: 20383195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20643727 | 1. Pediatrics. 2010 Aug;126(2):e391-400. doi: 10.1542/peds.2009-3491. Epub 2010
Jul 19.
Prevalence and complications of single-gene and chromosomal disorders in
craniosynostosis.
Wilkie AO(1), Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T,
Richards PG, Twigg SR, Wall SA.
Author information:
(1)Weatherall Institute of Molecular Medicine, John Radcliffe Hospital,
University of Oxford, Oxford, UK. [email protected]
OBJECTIVES: We describe the first cohort-based analysis of the impact of genetic
disorders in craniosynostosis. We aimed to refine the understanding of prognoses
and pathogenesis and to provide rational criteria for clinical genetic testing.
METHODS: We undertook targeted molecular genetic and cytogenetic testing for 326
children who required surgery because of craniosynostosis, were born in
1993-2002, presented to a single craniofacial unit, and were monitored until the
end of 2007.
RESULTS: Eighty-four children (and 64 relatives) had pathologic genetic
alterations (86% single-gene mutations and 14% chromosomal abnormalities). The
FGFR3 P250R mutation was the single largest contributor (24%) to the genetic
group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and
were associated with increased rates of many complications. Children with an
initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to
have a causative mutation if the synostoses were unicoronal or bicoronal (10 of
48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003).
Repeat craniofacial surgery was required for 58% of children with single-gene
mutations but only 17% of those with chromosomal abnormalities (P = .01).
CONCLUSIONS: Clinical genetic assessment is critical for the treatment of
children with craniosynostosis. Genetic testing of nonsyndromic cases (at least
for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with
coronal or multisuture synostoses. Single-gene disorders that disrupt
physiologic signaling in the cranial sutures often require reoperation, whereas
chromosomal abnormalities follow a more-indolent course, which suggests a
different, secondary origin of the associated craniosynostosis.
DOI: 10.1542/peds.2009-3491
PMCID: PMC3535761
PMID: 20643727 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16258006 | 1. J Med Genet. 2006 Jun;43(6):534-40. doi: 10.1136/jmg.2005.037820. Epub 2005
Oct 28.
Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene
and an evolutionarily conserved non-transcribed region.
Tagariello A, Heller R, Greven A, Kalscheuer VM, Molter T, Rauch A, Kress W,
Winterpacht A.
Craniosynostosis is a congenital developmental disorder involving premature
fusion of cranial sutures, which results in an abnormal shape of the skull.
Significant progress in understanding the molecular basis of this phenotype has
been made for a small number of syndromic craniosynostosis forms. Nevertheless,
in the majority of the approximately 100 craniosynostosis syndromes and in
non-syndromic craniosynostosis the underlying gene defects and pathomechanisms
are unknown. Here we report on a male infant presenting at birth with
brachycephaly, proptosis, midfacial hypoplasia, and low set ears. Three
dimensional cranial computer tomography showed fusion of the lambdoid sutures
and distal part of the sagittal suture with a gaping anterior fontanelle.
Mutations in the genes for FGFR2 and FGFR3 were excluded. Standard chromosome
analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The
breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in
skeletal growth and differentiation processes. SOX6 mutation screening of
another 104 craniosynostosis patients revealed one missense mutation leading to
the exchange of a highly conserved amino acid (p.D68N) in a single patient and
his reportedly healthy mother. The breakpoint on chromosome 9 is located in a
region without any known or predicted genes but, interestingly, disrupts patches
of evolutionarily highly conserved non-genic sequences and may thus led to
dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault
development. The present case is one of the very rare reports of an apparently
balanced translocation in a patient with syndromic craniosynostosis, and reveals
novel candidate genes for craniosynostoses and cranial suture formation.
DOI: 10.1136/jmg.2005.037820
PMCID: PMC2564540
PMID: 16258006 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: there are no competing
interests |
http://www.ncbi.nlm.nih.gov/pubmed/18000908 | 1. Am J Med Genet A. 2007 Dec 15;143A(24):2937-43. doi: 10.1002/ajmg.a.32092.
Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2
gene triplication.
Bernardini L(1), Castori M, Capalbo A, Mokini V, Mingarelli R, Simi P,
Bertuccelli A, Novelli A, Dallapiccola B.
Author information:
(1)CSS Hospital, IRCSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome,
Italy.
Craniosynostosis is a common birth defect ( approximately 1/3,000 births)
resulting from chromosome imbalances, gene mutations or unknown causes. We
report a 6-month-old female with multiple sutural synostosis and prenatal onset
growth deficiency, developmental delay, facial dysmorphism, congenital heart
defect, and inguinal hernia. An integrated approach of standard cytogenetics,
mBAND, locus-specific FISH, and 75 kb resolution array-CGH disclosed a complex
chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between-arm
insertions, and partial duplication of 5q35. An extra copy of the MSX2 gene,
which maps within the duplicated segment and is mutated in Boston-type
craniosynostosis, was confirmed by molecular cytogenetic studies. Our study
confirms that early fusion of cranial sutures commonly observed in the dup(5q)
syndrome is caused by triplication of the MSX2 gene and strongly supports the
crucial role of this gene in the development of craniofacial structures.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.32092
PMID: 18000908 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8476169 | 1. Ann Otol Rhinol Laryngol. 1993 Apr;102(4 Pt 1):285-8. doi:
10.1177/000348949310200407.
Pendred's syndrome.
Kabakkaya Y(1), Bakan E, Yiğitoğlu MR, Gökçe G, Doğan M.
Author information:
(1)Department of Otolaryngology, Orta Doğu Private Hospital, Erzurum, Turkey.
Although 5% of all cases of congenital deafness are caused by Pendred's
syndrome, there are few reports in the literature. Seven patients with Pendred's
syndrome in three families living in the same village were detected. For that
reason, the syndrome is reviewed in light of the literature. The sex
distribution of the patients with Pendred's syndrome and their families was
recorded. We tested for thyroxine, triiodothyronine, thyroid-stimulating
hormone, triiodothyronine resin uptake, and perchlorate, and performed caloric
testing. In one patient, subtotal thyroidectomy was performed. In the
histopathologic study, a thyroid nodule filled with colloid was found.
Chromosome studies showed no anomalies in any patient. Five of the patients were
deaf-mutes. We observed that the parents were cousins in all three families.
These families also had healthy children, and the existence of the syndrome in
both sexes points to an autosomal recessive trait.
DOI: 10.1177/000348949310200407
PMID: 8476169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21704276 | 1. J Mol Diagn. 2011 Jul;13(4):416-26. doi: 10.1016/j.jmoldx.2011.03.003. Epub
2011 Apr 29.
Mutation analysis of SLC26A4 for Pendred syndrome and nonsyndromic hearing loss
by high-resolution melting.
Chen N(1), Tranebjærg L, Rendtorff ND, Schrijver I.
Author information:
(1)Department of Pathology, Stanford University School of Medicine, Stanford,
California, USA.
Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital
deafness, locus 4) are associated with autosomal recessive congenital
sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic
heterogeneity, however, necessitates analysis of all exons and splice sites to
identify mutations for individual patients. Although Sanger sequencing is the
gold standard for mutation detection, screening methods supplemented with
targeted sequencing can provide a cost-effective alternative. One such method,
denaturing high-performance liquid chromatography, was developed for clinical
mutation detection in SLC26A4. However, this method inherently cannot
distinguish homozygous changes from wild-type sequences. High-resolution melting
(HRM), on the other hand, can detect heterozygous and homozygous changes
cost-effectively, without any post-PCR modifications. We developed a closed-tube
HRM mutation detection method specific for SLC26A4 that can be used in the
clinical diagnostic setting. Twenty-eight primer pairs were designed to cover
all 21 SLC26A4 exons and splice junction sequences. Using the resulting
amplicons, initial HRM analysis detected all 45 variants previously identified
by sequencing. Subsequently, a 384-well plate format was designed for up to
three patient samples per run. Blinded HRM testing on these plates of patient
samples collected over 1 year in a clinical diagnostic laboratory accurately
detected all variants identified by sequencing. In conclusion, HRM with targeted
sequencing is a reliable, simple, and cost-effective method for SLC26A4 mutation
screening and detection.
Copyright © 2011 American Society for Investigative Pathology and the
Association for Molecular Pathology. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.jmoldx.2011.03.003
PMCID: PMC3123795
PMID: 21704276 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16924389 | 1. J Hum Genet. 2006;51(9):805-810. doi: 10.1007/s10038-006-0027-z. Epub 2006 Aug
19.
Association of SLC26A4 mutations with clinical features and thyroid function in
deaf infants with enlarged vestibular aqueduct.
Iwasaki S(1), Tsukamoto K(2), Usami S(2), Misawa K(3), Mizuta K(3), Mineta H(3).
Author information:
(1)Department of Otolaryngology, Hamamatsu University School of Medicine,
1-20-1, Handayama, Hamamatsu city, 431-3192, Japan. [email protected].
(2)Department of Otolaryngology, Shinshu University School of Medicine, Shinshu,
Japan.
(3)Department of Otolaryngology, Hamamatsu University School of Medicine,
1-20-1, Handayama, Hamamatsu city, 431-3192, Japan.
Pendred syndrome and non-syndromic recessive deafness associated with enlarged
vestibular aqueduct (NSRD with EVA) are caused by mutations in the SLC26A4 (PDS)
gene. Unlike NSRD with EVA, Pendred syndrome is characterized by goiter, which
may be present after early adulthood. However, the clinical diagnosis of these
two disorders is difficult in deaf children. Expression of the SLC26A4 gene may
be responsible for iodide transport in the thyroid as well as for formation and
function of the inner ear. Here, we analyzed the SLC26A4 gene and performed
thyroid function tests (FT3, FT4, TSH, and Thyroglobulin) on six congenitally
deaf infants (mean age 2.7 years) with EVA. Mutation of the SLC26A4 gene was
identified in five patients: four were compound heterozygous (H723R/919-2A>G,
H723R/IVS15+5G>A, H723R/R581S, IVS7-2A>G/IVS8+1G>A), the fifth had a frameshift
mutation (322delC). All the patients demonstrated an elevation of serum
thyroglobulin level. FT3 level was elevated in four of the five patients. The
patient who did not have a detectable gene mutation showed normal thyroid
function. We conclude that the mutations in the SLC26A4 gene identified here are
highly associated with high serum thyroglobulin levels in congenital and
deafness infants. These mutations may be of value for the diagnosis of Pendred
syndrome and NSRD with EVA.
DOI: 10.1007/s10038-006-0027-z
PMID: 16924389 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22109890 | 1. Endocrinology. 2012 Jan;153(1):512-21. doi: 10.1210/en.2011-1548. Epub 2011
Nov 22.
TSH regulates pendrin membrane abundance and enhances iodide efflux in thyroid
cells.
Pesce L(1), Bizhanova A, Caraballo JC, Westphal W, Butti ML, Comellas A, Kopp P.
Author information:
(1)Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg
School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago,
Illinois 60611, USA.
Thyroid hormones are essential for normal development and metabolism. Their
synthesis requires transport of iodide into thyroid follicles. The mechanisms
involving the apical efflux of iodide into the follicular lumen are poorly
elucidated. The discovery of mutations in the SLC26A4 gene in patients with
Pendred syndrome (congenital deafness, goiter, and defective iodide
organification) suggested a possible role for the encoded protein, pendrin, as
an apical iodide transporter. We determined whether TSH regulates pendrin
abundance at the plasma membrane and whether this influences iodide efflux.
Results of immunoblot and immunofluorescence experiments reveal that TSH and
forskolin rapidly increase pendrin abundance at the plasma membrane through the
protein kinase A pathway in PCCL-3 rat thyroid cells. The increase in pendrin
membrane abundance correlates with a decrease in intracellular iodide as
determined by measuring intracellular (125)iodide and can be inhibited by
specific blocking of pendrin. Elimination of the putative protein kinase A
phosphorylation site T717A results in a diminished translocation to the membrane
in response to forskolin. These results demonstrate that pendrin translocates to
the membrane in response to TSH and suggest that it may have a physiological
role in apical iodide transport and thyroid hormone synthesis.
DOI: 10.1210/en.2011-1548
PMCID: PMC3249672
PMID: 22109890 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26236140 | 1. P T. 2015 Aug;40(8):511-20.
First-in-Class CDK4/6 Inhibitor Palbociclib Could Usher in a New Wave of
Combination Therapies for HR+, HER2- Breast Cancer.
McCain J.
Women with hormone receptor-positive, human epidermal growth factor receptor 2-
negative breast cancer-the most common subtype-have new options as palbociclib
and similar drugs debut. This article outlines the rationale and evidence for
their use.
PMCID: PMC4517534
PMID: 26236140 |
http://www.ncbi.nlm.nih.gov/pubmed/21274344 | 1. J Clin Res Pediatr Endocrinol. 2010;2(2):81-4. doi: 10.4274/jcrpe.v2i2.81.
Epub 2010 May 6.
Congenital goitrous hypothyroidism, deafness and iodide organification defect in
four siblings: Pendred or pseudo-Pendred syndrome?
Kara C(1), Kılıç M, Uçaktürk A, Aydın M.
Author information:
(1)Ondokuz Mayıs University, Faculty of Medicine, Pediatric Endocrinology,
Samsun, Turkey. [email protected]
Pendred syndrome (PDS) is an autosomal recessive disorder characterized by
congenital deafness, goiter and iodide organification defect. Presence of inner
ear malformations is essential for the clinical diagnosis. Most individuals with
PDS are clinically and biochemically euthyroid. Mutations in the PDS gene
encoding pendrin protein have been shown to be associated with PDS. It has been
recently demonstrated that some families with features of PDS do not have the
inner ear malformations and mutations in the PDS gene. This condition has been
named as "pseudo-Pendred syndrome" (pseudo-PDS), and has been hypothesized to be
of autoimmune origin. Here we report four siblings who have goiter, severe
hypothyroidism, a positive perchlorate discharge test and sensorineural
deafness, but not the inner ear abnormality which is diagnostic for PDS. We
suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo-PDS
patients with congenital goitrous hypothyroidism and deafness.
DOI: 10.4274/jcrpe.v2i2.81
PMCID: PMC3005669
PMID: 21274344 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18250610 | 1. J Endocrinol Invest. 2007 Dec;30(11):907-13. doi: 10.1007/BF03349236.
Two common and three novel PDS mutations in Thai patients with Pendred syndrome.
Snabboon T(1), Plengpanich W, Saengpanich S, Sirisalipoch S, Keelawat S,
Sunthornyothin S, Khovidhunkit W, Suwanwalaikorn S, Sridama V, Shotelersuk V.
Author information:
(1)Department of Internal Medicine, Faculty of Medicine, Chulalongkorn
University, Bangkok 10330, Thailand. [email protected]
Pendred syndrome is an autosomal recessive disorder characterized by congenital
sensorineural deafness, goiter, and impaired iodide organification. It is caused
by mutations in the PDS gene. Most published mutation studies of Pendred
syndrome have dealt with Western populations. In this study, we examined
clinical and molecular characteristics of 16 affected individuals in 6 unrelated
Thai families. Of all the affected, 100% (16/16) had bilateral deafness, 68.8%
(11/16) goiters, and 25% (4/16) hypothyroidism. Follicular thyroid carcinoma and
Hürthle cell adenoma were found in affected members of a family, raising the
possibility of an increased risk of thyroid carcinoma in Pendred syndrome
patients. Sequence analysis of the entire coding region of the PDS gene
successfully identified all 12 mutant alleles in these 6 families. The 12
identified mutant alleles constituted 6 distinct mutations including 3 splice
site mutations (IVS4-1G>A, IVS7-2A>G, IVS9- 1G>A), one frame shift mutation
(1548insC) and 2 missense mutations (T67S, H723R). Eight mutations out of 12
were constituted by IVS7- 2A>G and 1548insC, each one being present in 4
distinct alleles in our studied group. The identification of these two frequent
PDS mutations will facilitate the molecular diagnosis of Pendred syndrome in
Thai populations. In addition, three newly identified mutations, T67S,
IVS4-1G>A, and IVS9-1G>A, were not observed in 50 unrelated healthy Thai
controls.
DOI: 10.1007/BF03349236
PMID: 18250610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14727345 | 1. J Ayub Med Coll Abbottabad. 2003 Jul-Sep;15(3):59-64.
Syndromic and non-syndromic deafness, molecular aspects of Pendred syndrome and
its reported mutations.
Shaukat S(1), Fatima Z, Zehra U, Waqar AB.
Author information:
(1)National Centre of Excellence in Molecular Biology, University of the Punjab,
Lahore.
Deafness means partial or complete hearing impairment and is one of the most
prevalent sensory defects in humans. It can be due to genetic or environmental
causes or a combination of both and may be Syndromic (associated with additional
clinical features) or nonsyndromic (no other recognizable abnormal associated
phenotype). The overall impact of hearing impairment is greatly influenced by
the severity of hearing defect and by the age of onset. If defect is severe and
presents in early childhood, it has dramatic effect on speech acquisition and
thereby cognitive and psychosocial development. The mutations shown in the paper
results in the conformational changes of protein and influence the phenotype of
the affected individuals. For recessive cases of deafness it is possible to
reduce the incidence of deafness by carrier screening in the families with
multiple affected individuals and genetic counselling. Pendred Syndrome can be
characterized by the triad composed of familial goitre, abnormal perchlorate
discharge and congenital deafness.
PMID: 14727345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9070918 | 1. Genomics. 1997 Feb 15;40(1):48-54. doi: 10.1006/geno.1996.4541.
The gene for Pendred syndrome is located between D7S501 and D7S692 in a 1.7-cM
region on chromosome 7q.
Coucke P(1), Van Camp G, Demirhan O, Kabakkaya Y, Balemans W, Van Hauwe P, Van
Agtmael T, Smith RJ, Parving A, Bolder CH, Cremers CW, Willems PJ.
Author information:
(1)Department of Medical Genetics, University of Antwerp-UIA, Belgium.
Pendred syndrome is an autosomal recessive disorder characterized by goiter and
congenital deafness. The primary defect is not yet known, although the gene
causing Pendred syndrome has been localized very recently on chromosome 7q, a
region that also contains a gene responsible for nonsyndromal hearing loss
(DFNB4). We confirmed linkage to this chromosome 7 region in five Pendred
families originating from different ethnic groups, with a highest cumulative lod
score of 8.26 for marker D7S501. In combination with previous reports, our
results define a candidate region for the Pendred gene of 1.7 cM flanked by
markers D7S501 and D7S692.
DOI: 10.1006/geno.1996.4541
PMID: 9070918 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25488697 | 1. Drugs. 2015 Jan;75(1):33-59. doi: 10.1007/s40265-014-0337-y.
Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2
(SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.
Scheen AJ(1).
Author information:
(1)Division of Diabetes, Nutrition and Metabolic Disorders, Department of
Medicine, CHU Sart Tilman (B35), University of Liège, 4000, Liège, Belgium,
[email protected].
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a
novel approach for the management of type 2 diabetes mellitus (T2DM). Several
compounds are already available in many countries (dapagliflozin, canagliflozin,
empagliflozin and ipragliflozin) and some others are in a late phase of
development. The available SGLT2 inhibitors share similar pharmacokinetic
characteristics, with a rapid oral absorption, a long elimination half-life
allowing once-daily administration, an extensive hepatic metabolism mainly via
glucuronidation to inactive metabolites, the absence of clinically relevant
drug-drug interactions and a low renal elimination as parent drug. SGLT2
co-transporters are responsible for reabsorption of most (90 %) of the glucose
filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters
reduces hyperglycaemia by decreasing renal glucose threshold and thereby
increasing urinary glucose excretion. The amount of glucose excreted in the
urine depends on both the level of hyperglycaemia and the glomerular filtration
rate. Results of numerous placebo-controlled randomised clinical trials of
12-104 weeks duration have shown significant reductions in glycated haemoglobin
(HbA1c), resulting in a significant increase in the proportion of patients
reaching HbA1c targets, and a significant lowering of fasting plasma glucose
when SGLT2 inhibitors were administered as monotherapy or in addition to other
glucose-lowering therapies including insulin in patients with T2DM. In
head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar
glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The
durability of the glucose-lowering effect of SGLT2 inhibitors appears to be
better; however, this remains to be more extensively investigated. The risk of
hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and
was similarly low as that reported with metformin, pioglitazone or sitagliptin.
Increased renal glucose elimination also assists weight loss and could help to
reduce blood pressure. Both effects were very consistent across the trials and
they represent some advantages for SGLT2 inhibitors when compared with other
oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors
declines with increasing severity of renal impairment, and prescribing
information for each SGLT2 inhibitor should be consulted regarding dosage
adjustments or restrictions in moderate to severe renal dysfunction. Caution is
also recommended in the elderly population because of a higher risk of renal
impairment, orthostatic hypotension and dehydration, even if the absence of
hypoglycaemia represents an obvious advantage in this population. The overall
effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and
will be evaluated in several ongoing prospective placebo-controlled trials with
cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and
their potential to influence the course of diabetic nephropathy also deserve
more attention. SGLT2 inhibitors are generally well-tolerated. The most
frequently reported adverse events are female genital mycotic infections, while
urinary tract infections are less commonly observed and generally benign. In
conclusion, with their unique mechanism of action that is independent of insulin
secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic
options available for the management of T2DM at any stage in the natural history
of the disease. Although SGLT2 inhibitors have already been extensively
investigated, further studies should even better delineate the best place of
these new glucose-lowering agents in the already rich armamentarium for the
management of T2DM.
DOI: 10.1007/s40265-014-0337-y
PMID: 25488697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9398842 | 1. Nat Genet. 1997 Dec;17(4):411-22. doi: 10.1038/ng1297-411.
Pendred syndrome is caused by mutations in a putative sulphate transporter gene
(PDS).
Everett LA(1), Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E,
Nassir E, Baxevanis AD, Sheffield VC, Green ED.
Author information:
(1)Genome Technology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, Maryland 20892, USA.
Pendred syndrome is a recessively inherited disorder with the hallmark features
of congenital deafness and thyroid goitre. By some estimates, the disorder may
account for upwards of 10% of hereditary deafness. Previous genetic linkage
studies localized the gene to a broad interval on human chromosome 7q22-31.1.
Using a positional cloning strategy, we have identified the gene (PDS) mutated
in Pendred syndrome and found three apparently deleterious mutations, each
segregating with the disease in the respective families in which they occur. PDS
produces a transcript of approximately 5 kb that was found to be expressed at
significant levels only in the thyroid. The predicted protein, pendrin, is
closely related to a number of known sulphate transporters. These studies
provide compelling evidence that defects in pendrin cause Pendred syndrome
thereby launching a new area of investigation into thyroid physiology, the
pathogenesis of congenital deafness and the role of altered sulphate transport
in human disease.
DOI: 10.1038/ng1297-411
PMID: 9398842 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24309553 | 1. Chem Commun (Camb). 2014 Jan 28;50(8):1027-9. doi: 10.1039/c3cc47347c.
Highly specific enrichment of N-linked glycopeptides based on hydrazide
functionalized soluble nanopolymers.
Zhang L(1), Jiang H, Yao J, Wang Y, Fang C, Yang P, Lu H.
Author information:
(1)Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan
University, Shanghai 200032, China. [email protected].
In this work, for the first time, hydrazide functionalized PAMAM was designed
and synthesized for efficient and selective enrichment of N-linked glycopeptides
from complex biological samples using FASP (filter-aided sample preparation)
mode.
DOI: 10.1039/c3cc47347c
PMID: 24309553 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25962253 | 1. Harefuah. 2015 Mar;154(3):200-3, 210.
[SGLT2 inhibitors: a new therapeutic class for the treatment of type 2 diabetes
mellitus].
[Article in Hebrew]
Dagan A, Dagan B, SegaL G.
SGLT2 (Sodium Glucose co-Transporter 2 Inhibitors) inhibitors are a new group of
oral medications for the treatment of type 2 diabetes mellitus patients. These
medications interfere with the process of glucose reabsorption in the proximal
convoluted tubules in the kidneys, therefore increasing both glucose and water
diuresis. SGLT2 inhibitors were found to be effective in lowering HbA1c levels
in double-blinded studies, both as monotherapy and in combination with other
oral hypoglycemic medications of various other mechanisms of action. SGLT2
Inhibitors are not a risk factor for hypoglycemia and are suitable for
combination with insulin therapy. Their unique mode of action, relying on
glomerular filtration, make these medication unsuitable for usage as treatment
for type 2 diabetes patients who are also suffering from moderate to severe
renal failure. Their main adverse effects are increased risk for urinary and
genital tract infections. The following review describes the relevant
pathophysiology addressed by these novel medications, evidence for efficacy and
the safety profile of SGLT2 Inhibitors.
PMID: 25962253 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23807940 | 1. Drugs Today (Barc). 2013 Jun;49(6):363-76. doi: 10.1358/dot.2013.49.6.1965099.
Canagliflozin for the treatment of type 2 diabetes.
Babu A(1).
Author information:
(1)Department of Internal Medicine, Division of Endocrinology, John Stroger
Hospital of Cook County, Chicago, Illinois, USA. [email protected]
Canagliflozin, an oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in
the kidneys, leads to glucosuria and provides a unique mechanism to lower blood
glucose levels in diabetes. It corrects a novel pathophysiological defect, has
an insulin-independent action, reduces HbA1c by 0.5 to 1.1%, promotes weight
loss, has a low incidence of hypoglycemia, complements the action of other
antidiabetic agents, can be used at any stage of diabetes and appears to be safe
in patients with compromised renal function. Due to side effects such as urinary
tract and genital infections and decrease in blood pressure, proper patient
selection for drug initiation and close monitoring will be important. Results of
ongoing cardiovascular safety trials are important to determine the risk-benefit
ratio. Canagliflozin is the first oral SGLT2 inhibitor approved in the U.S.
market and it represents a promising approach for the treatment of diabetes in
this era of increasing obesity.
Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.
DOI: 10.1358/dot.2013.49.6.1965099
PMID: 23807940 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23214492 | 1. J Proteome Res. 2013 Feb 1;12(2):1040-8. doi: 10.1021/pr301009u. Epub 2012 Dec
24.
Combining filter-aided sample preparation and pseudoshotgun technology to
profile the proteome of a low number of early passage human melanoma cells.
Maurer M(1), Müller AC, Wagner C, Huber ML, Rudashevskaya EL, Wagner SN, Bennett
KL.
Author information:
(1)Division of Immunology, Allergy and Infectious Diseases, Department of
Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090
Vienna, Austria.
The performance of two proteomic sample preparation methods, "pseudoshotgun"
(PSG) and filter-aided sample preparation (FASP) were compared in terms of the
number of identified proteins, representation of cellular component GO (gene
ontology) categories in the obtained list of proteins, and the efficiency of
both methods in the proteomic analysis of a very low number of cells. Both
methods were combined to obtain a proteomic profile of a short-term culture
(passage 3) of melanoma cells, established in our laboratory from a human
metastatic melanoma lesion. The data revealed that with FASP, usually more
proteins are identified than with PSG when analyzing a higher number of cells (≥
5000/injection), whereas PSG is favorable when analyzing only a very small
amount of cells (250-500/injection). PSG and FASP, however, are complementary
techniques, as combining both methods further increases the number of identified
proteins. Moreover, we show that it is feasible to identify a substantial number
of proteins from only 250 cells/injection that is equivalent to 60 ng of
protein.
DOI: 10.1021/pr301009u
PMID: 23214492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24315007 | 1. Transplant Proc. 2013;45(10):3719-23. doi: 10.1016/j.transproceed.2013.08.079.
Urinary exosomes as a source of kidney dysfunction biomarker in renal
transplantation.
Alvarez S(1), Suazo C, Boltansky A, Ursu M, Carvajal D, Innocenti G, Vukusich A,
Hurtado M, Villanueva S, Carreño JE, Rogelio A, Irarrazabal CE.
Author information:
(1)Transplantation Unit, Davila Clinic, Santiago, Chile.
End-stage renal disease (ESRD) requires for its treatment permanent dialysis or
kidney transplantation (KT). KT is the best clinical treatment, however, the
early function of the allograft varies depending on multiple factors associated
with cold ischemia time (CIT) and the allograft rejection process. It is known
that serum creatinine is an insensitive and late marker for predicting graft
recovery after KT, mainly in patients with delayed graft function (DGF).
Neutrophil gelatinase-associated lipocalin (NGAL) is produced in the distal
nephron and it is one of the most promising novel biomarkers for acute kidney
injury (AKI) and chronic kidney disease (CKD). NGAL has been proposed to be a
predictor of organ recovery from DGF after KT from donors after cardiac death.
Because nonrenal diseases can also induce NGAL, more information is necessary to
validate the sensitivity and specificity of urine and plasma NGAL in clinical
samples. The exosomes are vesicles released into the urine from the kidney
epithelium and they have been proposed as better source to explore as biomarker
of renal dysfunction. The molecular composition of the urinary exosomes could be
representative of the physiological or physiopathologic condition of the urinary
system. We propose that determination of NGAL in urinary exosomes is a better
predictor of kidney dysfunction after KT than other urinary fractions. We
analyzed 15 kidney allograft recipients, with a mean age of 36 years (range,
16-60 years) and 75% were male: 11 living donors (LD) and 4 deceased donors
(DD). The average length of CIT was 14 hours in DD and less than 1 hour in LD.
Three patient developed DGF. Using Western blot analysis, NGAL was detectable in
the cellular and exosomal fraction of the urine. The exosomes expressed higher
levels of NGAL than the cellular fraction. The expression of NGAL was observed
from the first day after transplantation. In the cellular fraction of the urine,
no significant differences of NGAL were observed between the patients. However,
the median of NGAL expression in the exosomes fraction was significantly higher
in DD patient, from the first day after KT (P < .05). Moreover, we noticed that
NGAL expression in exosomes remained elevated in the patients with DGF compared
with non-DGF patients (P < .05). Considering the highest abundance of NGAL in
the urinary exosomes and its correlation with DGF patients, we suggest the
exosomal fraction as a more sensitive substrate to evaluate early biomarkers of
DGF after KT.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.transproceed.2013.08.079
PMID: 24315007 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22977310 | 1. Diabetes Metab Syndr Obes. 2012;5:313-27. doi: 10.2147/DMSO.S22545. Epub 2012
Aug 31.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the
management of type 2 diabetes.
Kim Y(1), Babu AR.
Author information:
(1)Division of Endocrinology, John, Stroger Jr Hospital of Cook County and Rush
University, Chicago, IL, USA.
BACKGROUND: The kidney plays an important role in glucose metabolism, and has
been considered a target for therapeutic intervention. The sodium-glucose
cotransporter type 2 (SGLT2) mediates most of the glucose reabsorption from the
proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a
unique mechanism to lower elevated blood glucose levels in diabetes. The purpose
of this review is to explore the physiology of SGLT2 and discuss several SGLT2
inhibitors which have clinical data in patients with type 2 diabetes.
METHODS: We performed a PubMed search using the terms "SGLT2" and "SGLT2
inhibitor" through April 10, 2012. Published articles, press releases, and
abstracts presented at national and international meetings were considered.
RESULTS: SGLT2 inhibitors correct a novel pathophysiological defect, have an
insulin-independent action, are efficacious with glycosylated hemoglobin
reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence
of hypoglycemia, complement the action of other antidiabetic agents, and can be
used at any stage of diabetes. They are generally well tolerated. However, due
to side effects, such as repeated urinary tract and genital infections,
increased hematocrit, and decreased blood pressure, appropriate patient
selection for drug initiation and close monitoring after initiation will be
important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors
on diabetic complications and cardiovascular safety are crucial to determine the
risk-benefit ratio. A recent decision by the Committee for Medicinal Products
for Human Use of the European Medicines Agency has recommended approval of
dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and
exercise, in combination with other glucose-lowering medicinal products,
including insulin, and as a monotherapy for metformin-intolerant patients.
Clinical research also remains to be carried out on the long-term effects of
glucosuria and other potential effects of SGLT2 inhibitors, especially in view
of the observed increase in the incidence of bladder and breast cancer. SGLT2
inhibitors represent a promising approach for the treatment of diabetes, and
could potentially be an addition to existing therapies.
DOI: 10.2147/DMSO.S22545
PMCID: PMC3437808
PMID: 22977310 |
http://www.ncbi.nlm.nih.gov/pubmed/24281781 | 1. Clin Chem. 2014 Mar;60(3):471-80. doi: 10.1373/clinchem.2013.210302. Epub 2013
Nov 26.
State of the art for measurement of urine albumin: comparison of routine
measurement procedures to isotope dilution tandem mass spectrometry.
Bachmann LM(1), Nilsson G, Bruns DE, McQueen MJ, Lieske JC, Zakowski JJ, Miller
WG.
Author information:
(1)Department of Pathology, Virginia Commonwealth University, Richmond, VA;
Comment in
Clin Chem. 2014 Mar;60(3):435-7. doi: 10.1373/clinchem.2013.218800.
BACKGROUND: Urine albumin is the primary biomarker for detection and monitoring
of kidney damage. Because fixed decision criteria are used to identify patients
with increased values, we investigated if commonly used routine measurement
procedures gave comparable results.
METHODS: Results from 17 commercially available urine albumin measurement
procedures were investigated vs an isotope dilution mass spectrometry (IDMS)
procedure. Nonfrozen aliquots of freshly collected urine from 332 patients with
chronic kidney disease, diabetes, cardiovascular disease, and hypertension were
distributed to manufacturers to perform urine albumin measurements according to
the respective instructions for use for each procedure. Frozen aliquots were
used for measurements by the IDMS procedure. An error model was used to
determine imprecision and bias components.
RESULTS: Median differences between the largest positive and negative biases vs
IDMS were 45%, 37%, and 42% in the concentration intervals of 12-30 mg/L, 31-200
mg/L, and 201-1064 mg/L, respectively. Biases varied with concentration for most
procedures and exceeded ± 10% over the concentration interval for 14 of 16
quantitative procedures. Mean biases ranged from -35% to 34% at 15 mg/L.
Dilution of samples with high concentrations introduced bias for 4 procedures.
The combined CV was >10% for 5 procedures. It was not possible to estimate total
error due to dependence of bias on concentration. CVs for sample-specific
influences were 0% to 15.2%.
CONCLUSIONS: Bias was the dominant source of disagreement among routine
measurement procedures. Consequently, standardization efforts will improve
agreement among results. Variation of bias with concentration needs to be
addressed by manufacturers.
DOI: 10.1373/clinchem.2013.210302
PMID: 24281781 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20425065 | 1. Curr Diab Rep. 2010 Feb;10(1):37-42. doi: 10.1007/s11892-009-0080-z.
The emerging role of biomarkers in diabetic and hypertensive chronic kidney
disease.
Chaudhary K(1), Phadke G, Nistala R, Weidmeyer CE, McFarlane SI, Whaley-Connell
A.
Author information:
(1)Department of Internal Medicine, Division of Nephrology and Hypertension,
University of Missouri-Columbia School of Medicine, CE417, DC043.0, Five
Hospital Drive, Columbia, MO 65212, USA.
Currently used measures to assess kidney function and injury are largely
inadequate. Markers such as serum creatinine, formulas to estimate glomerular
filtration rate, cystatin C, and proteinuria largely identify an underlying
disease process that is well established. Thus, there has been a recent effort
to identify new biomarkers that reflect kidney function, early injury, and/or
repair that ultimately can relate to progression or regression of damage.
Several biomarkers emerged recently that are able to detect kidney damage
earlier than is currently possible with traditional biomarkers such as serum
creatinine and proteinuria. Identification of urine biomarkers has proven to be
beneficial in recent years because of ease of handling, stability, and the
ability to standardize the various markers to creatinine or other peptides
generally already present in the urine. Recent markers such as neutrophil
gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and
podocin have garnered a lot of attention. The emergence of these and other
biomarkers is largely because of the evolution of novel genomic and proteomic
applications in investigations of acute kidney injury and chronic kidney
disease. In this article, we focus on the applications of these biomarkers in
disease.
DOI: 10.1007/s11892-009-0080-z
PMID: 20425065 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24455799 | 1. Acta Clin Belg. 2013 Jul-Aug;68(4):287-93. doi: 10.2143/ACB.3349.
SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes
introduction of SGLT2-inhibitors in clinical practice.
Cuypers J(1), Mathieu C(2), Benhalima K(2).
Author information:
(1)Department of Internal Medicine, UZ Gasthuisberg, KU Leuven, Belgium.
(2)Department of Endocrinology, UZ Gasthuisberg, KU Leuven, Belgium.
Treatment of type 2 diabetes (T2DM) continues to present challenges, with
significant proportion of patients failing to achieve and maintain glycemic
targets. Despite the availability of many oral antidiabetic agents, therapeutic
efficacy is offset by side effects such as weight gain and hypoglycemia.
Therefore, the search for novel therapeutic agents with an improved benefit-risk
profile continues. Recent research has focused on the kidney as a potential
therapeutic target, especially because maximal renal glucose reabsorption is
increased in T2DM. Under normal physiological conditions, nearly all filtered
glucose is reabsorbed in the proximal tubule of the nephron, principally via the
sodium-glucose cotransporter 2 (SGLT2). SGLT2-inhibitors are a new class of oral
antidiabetics, which reduce hyperglycemia by increasing urinary glucose
excretion independently of insulin secretion or action. Clinical results are
promising with significant lowering of HbA1c without increased risk of
hypoglycemia, reduction of body weight and reduction of systolic blood pressure.
Dapagliflozin is the first highly selective SGLT2-inhibitor approved by the
European Medecine Agency. Canagliflozin and empagliflozin are undergoing phase
III trials. Actual safety issues are an increased risk for genital- and urinary
tract infections and a possible increased risk for bladder and breast cancer.
This led to refusal of dapagliflozin by the Food and Drug Administration (FDA).
A large randomized control trial is therefore warranted by the FDA. This review
provides an overview of the current evidence available so far on the therapeutic
potential of the SGLT2-inhibitors for the treatment of T2DM.
DOI: 10.2143/ACB.3349
PMID: 24455799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22092713 | 1. FEMS Microbiol Lett. 2011 Oct;323(2):142-50. doi:
10.1111/j.1574-6968.2011.02370.x. Epub 2011 Aug 25.
Quantitative proteomics of Chlorobaculum tepidum: insights into the sulfur
metabolism of a phototrophic green sulfur bacterium.
Falkenby LG(1), Szymanska M, Holkenbrink C, Habicht KS, Andersen JS, Miller M,
Frigaard NU.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Southern
Denmark, Odense, Denmark.
Chlorobaculum (Cba.) tepidum is a green sulfur bacterium that oxidizes sulfide,
elemental sulfur, and thiosulfate for photosynthetic growth. To gain insight
into the sulfur metabolism, the proteome of Cba. tepidum cells sampled under
different growth conditions has been quantified using a rapid gel-free,
filter-aided sample preparation (FASP) protocol with an in-solution isotopic
labeling strategy. Among the 2245 proteins predicted from the Cba. tepidum
genome, approximately 970 proteins were detected in unlabeled samples, whereas
approximately 630-640 proteins were detected in labeled samples comparing two
different growth conditions. Wild-type cells growing on thiosulfate had an
increased abundance of periplasmic cytochrome c-555 and proteins of the
periplasmic thiosulfate-oxidizing SOX enzyme system when compared with cells
growing on sulfide. A dsrM mutant of Cba. tepidum, which lacks the dissimilatory
sulfite reductase DsrM protein and therefore is unable to oxidize sulfur
globules to sulfite, was also investigated. When compared with wild type, the
dsrM cells exhibited an increased abundance of DSR enzymes involved in the
initial steps of sulfur globule oxidation (DsrABCL) and a decreased abundance of
enzymes putatively involved in sulfite oxidation (Sat-AprAB-QmoABC). The results
show that Cba. tepidum regulates the cellular levels of enzymes involved in
sulfur metabolism and other electron-transferring processes in response to the
availability of reduced sulfur compounds.
© 2011 Federation of European Microbiological Societies. Published by Blackwell
Publishing Ltd. All rights reserved.
DOI: 10.1111/j.1574-6968.2011.02370.x
PMID: 22092713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23061738 | 1. Biomarkers. 2012 Dec;17(8):714-20. doi: 10.3109/1354750X.2012.722229. Epub
2012 Oct 15.
Urinary mRNA expression of CCN2/CCN3 as a noninvasive marker for monitoring
glomerular structure changes in nondiabetic chronic kidney disease.
Chen L(1), Wu YG, Liu D, Lv LL, Zheng M, Ni HF, Cao YH, Liu H, Zhang P, Zhang
JD, Liu BC.
Author information:
(1)Institute of Nephrology, Division of Nephrology, Zhongda Hospital, School of
Medicine, Southeast University, Nanjing, China.
BACKGROUND: We investigated whether urinary mRNA of connective tissue growth
factor (CCN2) and nephroblastoma overexpressed gene (CCN3) can provide clinical
insight into the management of patients with nondiabetic CKD.
METHODS: Urinary mRNA expression of CCN2 and CCN3 were measured by Real-time PCR
in 35 CKD patients and 12 controls.
RESULTS: Urinary mRNA of CCN2 and CCN3 were distinctively greater in CKDs than
healthy controls. Urinary CCN3/CCN2 mRNA ratio correlated to the degree of
glomerular histological changes in those who received renal biopsy.
CONCLUSION: Urinary CCN3/CCN2 mRNA ratio may be a useful noninvasive biomarker
for evaluating patients with nondiabetic CKD prior to renal biopsy.
DOI: 10.3109/1354750X.2012.722229
PMID: 23061738 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24825435 | 1. Cardiovasc Drugs Ther. 2014 Aug;28(4):331-4. doi: 10.1007/s10557-014-6522-0.
Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic
drugs.
Opie LH(1).
Author information:
(1)University of Cape Town Medical School, Cape Town, South Africa,
[email protected].
Type 2 diabetes is characterized by decreased insulin secretion and sensitivity.
The available oral anti-diabetic drugs act on many different molecular sites.
The most used of oral anti-diabetic agents is metformin that activates glucose
transport vesicles to the cell surface. Others are: the sulphonylureas; agents
acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors;
meglinitide analogues; and the thiazolidinediones. Despite these many drugs
acting by different mechanisms, glycaemic control often remains elusive. None of
these drugs have a primary renal mechanism of action on the kidneys, where
almost all glucose excreted is normally reabsorbed. That is where the inhibitors
of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site
of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a
new principle of control in type 2 diabetes that has several advantages with
some urogenital side-effects, both of which are evaluated in this review.
Specific approvals include use as monotherapy, when diet and exercise alone do
not provide adequate glycaemic control in patients for whom the use of metformin
is considered inappropriate due to intolerance or contraindications, or as
add-on therapy with other anti-hyperglycaemic medicinal products including
insulin, when these together with diet and exercise, do not provide adequate
glycemic control. The basic mechanisms are improved β-cell function and insulin
sensitivity. When compared with sulphonylureas or other oral antidiabetic
agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital
side-effects related to the enhanced glycosuria can be troublesome, yet seldom
lead to discontinuation. On this background, studies are analysed that compare
SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of
action, unloading the excess glycaemic load, contrasts with other oral agents
that all act to counter the effects of diabetic hyperglycaemia.
DOI: 10.1007/s10557-014-6522-0
PMID: 24825435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23042029 | 1. Curr Opin Nephrol Hypertens. 2013 Jan;22(1):113-9. doi:
10.1097/MNH.0b013e32835a17ae.
Sodium glucose cotransporter 2 and the diabetic kidney.
Komala MG(1), Panchapakesan U, Pollock C, Mather A.
Author information:
(1)Renal laboratory, Kolling Institute of Medical Research, University of
Sydney, Sydney, Australia.
PURPOSE OF REVIEW: Reabsorption of glucose in the proximal tubule occurs
predominantly via the sodium glucose cotransporter 2 (SGLT2). There has been
intense interest in this transporter as a number of SGLT2 inhibitors have
entered clinical development. SGLT2 inhibitors act to lower plasma glucose by
promoting glycosuria and this review aims to outline the effect on the diabetic
kidney of this hypoglycaemic agent.
RECENT FINDINGS: This review provides an overview of recent findings in this
area: the transcriptional control of SGLT2 expression in human proximal tubular
cells implicates a number of cytokines in the alteration of SGLT2 expression;
experimental data show that SGLT2 inhibition may correct early detrimental
effects of diabetes by reducing proximal tubular sodium and glucose transport,
suggesting a possible renoprotective effect independent of the glucose lowering
effects of these agents; and the nonglycaemic effects of SGLT2 inhibitors may
have an impact on renal outcomes.
SUMMARY: The available clinical evidence shows consistent reduction in glycaemic
parameters and some evidence suggests additional effects including weight loss
and mild blood pressure reduction. There are some side effects that warrant
further investigation and establishing whether SGLT2 inhibition provides a renal
benefit relies on future long-term studies with specific renal end-points.
DOI: 10.1097/MNH.0b013e32835a17ae
PMID: 23042029 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24341330 | 1. BMC Endocr Disord. 2013 Dec 17;13:58. doi: 10.1186/1472-6823-13-58.
Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes
mellitus: a meta-analysis of randomized double-blind controlled trials.
Berhan A(1), Barker A.
Author information:
(1)Hawassa University College of Medicine and Health Sciences, P, O, Box: 1560,
Hawassa, Ethiopia. [email protected].
BACKGROUND: The discovery of sodium-glucose co-transporter 2 (SGLT2) inhibitors,
with a novel mechanism independent of insulin secretion or sensitization, bring
about a new therapeutic approach to the management of type 2 diabetes mellitus.
The aim of this meta-analysis was to evaluate the safety and efficacy of SGLT2
inhibitors at different doses in randomized double blind clinical trials.
METHODS: This meta-analysis was conducted by including randomized double-blind
controlled trials of SGLT2 inhibitors in patients with type 2 diabetes
irrespective of their antidiabetic drug exposure history but with an inadequate
glycemic control. All the effect sizes were computed using the random effects
model. Standardized mean differences (SMDs) and odds ratios (OR) were computed
for continuous and dichotomous variables, respectively. Additional analyses like
sensitivity analysis, subgroup analysis and meta-regression were also performed.
RESULTS: The pooled analyses demonstrated a significant reduction in mean
changes in Hemoglobin A1c (HbA1c) (SMD = -0.78%, 95% CI, -0.87 to -0.69),
fasting plasma glucose (FPG) (SMD = -0.70 mg/dl, 95% CI, -0.79 to -0.61), body
weight (overall SMD = -0.59 kg, 95% CI, -0.65 to -0.52) and blood pressure from
baseline with SGLT2 inhibitors based therapy. Consistently a significant number
of patients treated with SGLT2 inhibitors achieved HbA1c < 7% (OR = 2.09, 95%
CI, 1.77 to 2.46). SGLT2 inhibitors based therapy was associated with adverse
events like genital and urinary tract infections.
CONCLUSION: All studied doses of SGLT2 inhibitors, either as monotherapy or in
combination with other antidiabetic agents, consistently improved glycemic
control in patients with type 2 diabetes. However, a small percentage of
patients suffer from genital and urinary tract infections.
DOI: 10.1186/1472-6823-13-58
PMCID: PMC3883465
PMID: 24341330 |
http://www.ncbi.nlm.nih.gov/pubmed/21467162 | 1. Clin Cancer Res. 2011 May 1;17(9):2900-7. doi: 10.1158/1078-0432.CCR-10-3069.
Epub 2011 Apr 5.
Excellent prognosis in a subset of patients with Ewing sarcoma identified at
diagnosis by CD56 using flow cytometry.
Ash S(1), Luria D, Cohen IJ, Goshen Y, Toledano H, Issakov J, Yaniv I, Avigad S.
Author information:
(1)Department of Pediatric Hematology-Oncology, Schneider Children's Medical
Center of Israel, Petach Tikva, Israel. [email protected]
PURPOSE: Ewing sarcoma (ES) is considered a systemic disease with the majority
of patients harboring micrometastases at diagnosis. Multiparameter flow
cytometry (MPFC) was used to detect ES cells in bone marrow (BM) of ES patients
at diagnosis and to evaluate the prognostic significance of CD56 expression in
BM samples.
EXPERIMENTAL DESIGN: BM samples from 46 ES patients, 6 tumor aspirates, 2 ES
cell lines, and 10 control BM samples were analyzed by MPFC. ES cells were
identified by the combination of CD45-/CD90+/CD99+. CD56 was evaluated on these
cells by a cutoff of 22%.
RESULTS: BM samples obtained from all patients at diagnosis were found to be
positive for micrometastatic tumor cells assessed by CD99+/CD90+/CD45-
expression. A total of 60% of the BM samples harbored high CD56 expression.
There was a highly significant correlation between CD56 expression and
progression-free survival (PFS; 69% in low/negative expression versus 30% in
high expression groups, P = 0.024). In patients with localized nonpelvic
disease, those expressing low/negative CD56 had 100% PFS versus 40% in the high
expressing group (P = 0.02). By Cox regression analysis, CD56 was found to be an
independent prognostic marker with an 11-fold increased risk for relapse in
patients with localized disease (P = 0.006).
CONCLUSION: All samples contained cells that are positive for the
CD99+/CD90+/CD45- combination at diagnosis, indicating that ES is a systemic
disease. CD56 expression could be used to reveal ES patients with excellent
prognosis or patients predisposed to relapse, thus improving treatment
stratification and implementation of personalized therapy.
©2011 AACR.
DOI: 10.1158/1078-0432.CCR-10-3069
PMID: 21467162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22914685 | 1. Curr Opin Nephrol Hypertens. 2012 Nov;21(6):619-27. doi:
10.1097/MNH.0b013e32835846e3.
Biomarkers in native and transplant kidneys: opportunities to improve prediction
of outcomes in chronic kidney disease.
De Serres SA(1), Varghese JC, Levin A.
Author information:
(1)Transplantation Unit, Renal Division, Department of Medicine, CHUQ
L'Hôtel-Dieu de Québec, Université Laval, Québec, Quebec, Canada.
PURPOSE OF REVIEW: Predicting the outcomes of patients with chronic kidney
disease (CKD) is important from both patient and healthcare system perspectives.
This review examines the current state of conventional and nonconventional
biomarkers as noninvasive tools to improve risk-stratification and outcome
prediction in CKD.
RECENT FINDINGS: Conventional biomarkers (serum creatinine, urine albumin, and
clinical variables such as sex, age, and diabetes) have been the cornerstone of
most prediction models for CKD progression to end-stage renal disease (ESRD),
and adverse cardiovascular outcomes including death. With better understanding
of the pathophysiology of CKD and the evolution of molecular diagnostics,
numerous novel or nonconventional markers have emerged. They have been examined
individually and in combination to predict specific outcomes. We highlight these
markers and studies, conducted primarily in patients with native kidneys. In
those with transplant kidneys, markers of both acute and chronic kidney
dysfunction have been examined, although to a lesser extent. Similarities and
differences in knowledge derived from these two populations are highlighted.
SUMMARY: Improving prediction of outcomes in CKD patients with either native or
transplant kidneys remains an important goal. Increasingly sophisticated
biomarkers may potentially identify targets for clinical research, improve the
nature and timing of therapeutic interventions, and guide resource allocation.
DOI: 10.1097/MNH.0b013e32835846e3
PMID: 22914685 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23354439 | 1. Nat Genet. 2013 Mar;45(3):308-13. doi: 10.1038/ng.2539. Epub 2013 Jan 27.
Reduced dosage of ERF causes complex craniosynostosis in humans and mice and
links ERK1/2 signaling to regulation of osteogenesis.
Twigg SR(1), Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M,
Zaragkoulias A, Sadighi Akha E, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK,
Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P,
Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO.
Author information:
(1)Clinical Genetics Group, Weatherall Institute of Molecular Medicine,
University of Oxford, Oxford, UK.
The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins
mediating mitogen-activated protein kinase signaling downstream of RAS:
phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple
targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory
ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes
complex craniosynostosis (premature fusion of the cranial sutures) in humans and
mice. Features of this newly recognized clinical disorder include
multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and
language delay. Mice with functional Erf levels reduced to ∼30% of normal
exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial
development appears mildly delayed. Using chromatin immunoprecipitation in mouse
embryonic fibroblasts and high-throughput sequencing, we find that ERF binds
preferentially to elements away from promoters that contain RUNX or AP-1 motifs.
This work identifies ERF as a novel regulator of osteogenic stimulation by
RAS-ERK signaling, potentially by competing with activating ETS factors in
multifactor transcriptional complexes.
DOI: 10.1038/ng.2539
PMCID: PMC3683605
PMID: 23354439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24631482 | 1. J Am Soc Hypertens. 2014 May;8(5):330-9. doi: 10.1016/j.jash.2014.02.003. Epub
2014 Feb 12.
Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.
Oliva RV(1), Bakris GL(2).
Author information:
(1)Department of Medicine, Philippine General Hospital, Manila, Philippines.
(2)ASH Comprehensive Hypertension Center, The University of Chicago Medicine,
Chicago, IL, USA. Electronic address: [email protected].
Management of hypertension in diabetes is critical for reduction of
cardiovascular mortality and morbidity. While blood pressure (BP) control has
improved over the past two decades, the control rate is still well below 50% in
the general population of patients with type 2 diabetes mellitus (T2DM). A new
class of oral glucose-lowering agents has recently been approved; the
sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating
large amounts of glucose in the urine. Two agents, dapagliflozin and
canagliflozin, are currently approved in the United States and Europe, and
empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to
glucose lowering, SGLT2 inhibitors are associated with weight loss and act as
osmotic diuretics, resulting in a lowering of BP. While not approved for
BP-lowering, they may potentially aid BP goal achievement in people within 7-10
mm Hg of goal. It should be noted that the currently approved agents have side
effects that include an increased incidence of genital infections, predominantly
in women. The approved SGLT2 inhibitors have limited use based on kidney
function and should be used only in those with an estimated glomerular
filtration rate (eGFR) > 60 mL/min/1.73 m2 for dapagliflozin and ≥45 mL/min/1.73
m2 for canagliflozin. Cardiovascular outcome trials are ongoing with these
agents and will be completed within the next 4-5 years.
Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc.
All rights reserved.
DOI: 10.1016/j.jash.2014.02.003
PMID: 24631482 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9692823 | 1. Virchows Arch. 1998 Jul;433(1):35-40. doi: 10.1007/s004280050213.
Identification of CD56 and CD57 by flow cytometry in Ewing's sarcoma or
primitive neuroectodermal tumor.
Gardner LJ(1), Polski JM, Fallon R, Dunphy CH.
Author information:
(1)Department of Pathology, Saint Louis University Health Sciences Center, MO,
USA.
CD56 and CD57 are commonly considered as natural killer and neuroectodermal
markers, but their expression has been identified in a wide spectrum of
neoplasms including some cases of Ewing's sarcoma (ES) and primitive
neuroectodermal tumor (PNET). We report two cases of small, round blue cell
tumor (SRBCT), in which flow cytometry immunophenotyping (FCI) detected strong
expression of CD56 and CD57 (one case). Immunohistochemical staining with Leu-19
and Leu-7 confirmed the FI results. Although CD56 and CD57 expression is
consistent with ES/PNET, it can be potentially misleading if results of FCI are
interpreted in the absence of other findings. These cases suggest the utility of
FCI in undifferentiated SRBCT. The literature on CD56 and CD57 expression in
ES/PNET is reviewed and discussed.
DOI: 10.1007/s004280050213
PMID: 9692823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19895697 | 1. BMC Musculoskelet Disord. 2009 Nov 6;10:136. doi: 10.1186/1471-2474-10-136.
Does physical activity change predict functional recovery in low back pain?
Protocol for a prospective cohort study.
Hendrick P(1), Milosavljevic S, Bell ML, Hale L, Hurley DA, McDonough SM, Melloh
M, Baxter DG.
Author information:
(1)Centre for Physiotherapy Research, School of Physiotherapy, University of
Otago, Dunedin, New Zealand. [email protected]
BACKGROUND: Activity advice and prescription are commonly used in the management
of low back pain (LBP). Although there is evidence for advising patients with
LBP to remain active, facilitating both recovery and return to work, to date no
research has assessed whether objective measurements of free living physical
activity (PA) can predict outcome, recovery and course of LBP.
METHODS: An observational longitudinal study will investigate PA levels in a
cohort of community-dwelling working age adults with acute and sub-acute LBP.
Each participant's PA level, functional status, mood, fear avoidance behaviours,
and levels of pain, psychological distress and occupational activity will be
measured on three occasions during for 1 week periods at baseline, 3 months, and
1 year. Physical activity levels will be measured by self report, RT3 triaxial
accelerometer, and activity recall questionnaires. The primary outcome measure
of functional recovery will be the Roland Morris Disability Questionnaire
(RMDQ). Free living PA levels and changes in functional status will be
quantified in order to look at predictive relationships between levels and
changes in free living PA and functional recovery in a LBP population.
DISCUSSION: This research will investigate levels and changes in activity levels
of an acute LBP cohort and the predictive relationship to LBP recovery. The
results will assess whether occupational, psychological and behavioural factors
affect the relationship between free living PA and LBP recovery. Results from
this research will help to determine the strength of evidence supporting
international guidelines that recommend restoration of normal activity in
managing LBP.
TRIAL REGISTRATION: [Clinical Trial Registration Number, ACTRN12609000282280].
DOI: 10.1186/1471-2474-10-136
PMCID: PMC2777147
PMID: 19895697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19945334 | 1. Man Ther. 2010 Apr;15(2):185-9. doi: 10.1016/j.math.2009.10.007. Epub 2009 Nov
27.
The relationship between psychological distress and free-living physical
activity in individuals with chronic low back pain.
Ryan CG(1), Gray HG, Newton M, Granat MH.
Author information:
(1)School of Health, Glasgow Caledonian University, G4 0BA, Scotland, UK.
[email protected]
The aim of this cross-sectional pilot-study was to investigate the relationship
between psychological distress and free-living physical activity (PA) in
individuals with chronic low back pain (CLBP). Thirty-eight participants with
non-specific CLBP (29=distressed; 9=non-distressed) were recruited. PA levels
were measured using an accelerometer (activPAL activity monitor) over a one week
period. The following parameters of physical activity were recorded: time
upright (standing or walking), time standing, time walking, and step count.
Psychological distress was assessed using a modified version of the distress
risk assessment method (DRAM) which is a combination of somatic anxiety and
depressive symptoms. The Distressed group spent significantly less time upright
over a mean 24h day (-1.47h, 95% CI -2.70 to -0.23h, p<0.05), attributable to
1.01h less standing and 0.46h less walking. Depressive symptoms were a
statistically significant independent predictor of time upright (beta=-0.49,
p<0.05). This pilot-study found that individuals with CLBP and elevated levels
of distress spend less time upright than their non-distressed counterparts.
Clinically, when treating individuals with CLBP and elevated distress levels,
free-living PA may be low and interventions aimed at increasing upright activity
may be appropriate.
Copyright 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.math.2009.10.007
PMID: 19945334 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18752975 | 1. Eur J Pain. 2009 Jul;13(6):649-54. doi: 10.1016/j.ejpain.2008.07.005. Epub
2008 Aug 26.
Daily physical activities in chronic lower back pain patients assessed with
accelerometry.
van Weering MG(1), Vollenbroek-Hutten MM, Tönis TM, Hermens HJ.
Author information:
(1)Roessingh Research and Development, Enschede, The Netherlands.
[email protected]
BACKGROUND: Normalization of activities in daily living is an important goal in
rehabilitation treatment of chronic lower back pain (CLBP) patients. Clinicians
indicate that CLBP patients often show deconditioning but also CLBP patients who
seem to be too active are seen. The objective of the present cross-sectional
study was to gain more insight into the daily activity pattern of CLBP patients
compared to controls, using accelerometry.
METHODS: Daily activities were assessed by measuring body movement with a
tri-axial accelerometer that was worn for seven consecutive days during waking
hours. Measurements were performed in the daily environment (in-doors and
out-doors) of the participant. Differences between activity level, time of day
and work status were tested.
RESULTS: Data were obtained from 29 CLBP patients and 20 controls. Results show
that the overall activity levels of patients (mean 0.75; SD 0.43) are not
significantly different from those of controls (mean 0.71; SD 0.44). However,
patients show significantly higher activity levels in the morning (p<0.001) and
significantly lower activity levels in the evening (p<0.01) compared to
controls. No significant differences in activity levels were found between
leisure time and working days within either group; furthermore no significant
differences in activity levels were found between patients with different work
status.
CONCLUSION: Overall activity levels do not differ significantly between CLBP
patients and controls, but the distribution of activities over the day differs
significantly.
DOI: 10.1016/j.ejpain.2008.07.005
PMID: 18752975 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23865908 | 1. Disabil Rehabil. 2014;36(9):749-55. doi: 10.3109/09638288.2013.814723. Epub
2013 Jul 18.
Physical activity and low back pain: the role of subgroups based on the
avoidance-endurance model.
Plaas H(1), Sudhaus S, Willburger R, Hasenbring MI.
Author information:
(1)Department of Medical Psychology and Medical Sociology, Faculty of Medicine,
Ruhr-University of Bochum , Bochum , Germany and.
PURPOSE: This study examines the relationship between low back pain, disability
and fatigue and overt physical activity with respect to fear-avoidance and
endurance-related subgroups.
METHOD: 49 patients completed questionnaires (Pain, Disability, Fatigue,
Depression, Pain-responses pattern) 6 months after lumbar disc surgery and
underwent an 8-hour accelerometer assessment measuring overall physical activity
(PAL), constant strain postures (CSP), standing time (ST) and lying time (LT).
Four subgroups, representing patterns of distress-endurance (DER),
eustress-endurance (EER), fear-avoidance (FAR) and adaptive responses (AR) due
to the avoidance-endurance model of pain-regulation were investigated.
RESULTS: Multivariate analyses of covariance revealed significantly higher pain,
disability and fatigue in FAR compared to AR patients and, as expected lower PAL
and CSP in FAR than in endurance patients. Both endurance groups revealed higher
pain accompanied by higher accelerometer-based physical activity (PAL, CSP) than
AR and FAR patients. Most of the subgroup differences displayed moderate to high
effect sizes.
CONCLUSIONS: The results indicate different pathways to chronic pain and
disability with physical underuse in FAR patients and overuse/overload in
endurance patients suggesting the need for individually targeted
cognitive-behavioral treatments in the maladaptive groups. Implications for
Rehabilitation Improving the return to a normal physical activity level is an
important goal for the rehabilitation of patients after lumbar disc surgery.
Different pathways to chronic pain and disability with physical underuse in
fear-avoidance patients and overuse in endurance patients should be considered.
Different pain-related pain response pattern, based on the avoidance-endurance
model, indicate the need for individual targeting of rehabilitation programs.
DOI: 10.3109/09638288.2013.814723
PMID: 23865908 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23339563 | 1. Biomarkers. 2013 Mar;18(2):103-15. doi: 10.3109/1354750X.2012.749302. Epub
2013 Jan 23.
Clinical and research markers of oxidative stress in chronic kidney disease.
Tucker PS(1), Dalbo VJ, Han T, Kingsley MI.
Author information:
(1)Clinical Biochemistry Laboratory, Institute for Health and Social Science
Research, Central Queensland University, Rockhampton, QLD, Australia.
CONTEXT: Kidney-related pathologies have increasing prevalence rates, produce a
considerable financial burden, and are characterized by elevated levels of
oxidative stress (OS).
OBJECTIVE: This review examines relationships between chronic kidney disease
(CKD) and markers of OS and antioxidant status (AS).
METHODS: A systematic review of MEDLINE-indexed clinical trials, randomized
controlled trials and comparative studies that examined OS and AS was performed.
RESULTS AND CONCLUSION: Several markers emerged as well-suited indicators of OS
and AS in CKD: malondialdehyde, F2-isoprostanes, lipid hydroperoxides,
asymmetric dimethylarginine, 8-oxo-7,8-dihydro-2'-deoxyguanosine, protein
carbonyls, advanced oxidation protein products and glutathione-related activity.
DOI: 10.3109/1354750X.2012.749302
PMID: 23339563 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16381983 | 1. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D95-7. doi:
10.1093/nar/gkj115.
A new generation of JASPAR, the open-access repository for transcription factor
binding site profiles.
Vlieghe D(1), Sandelin A, De Bleser PJ, Vleminckx K, Wasserman WW, van Roy F,
Lenhard B.
Author information:
(1)Department for Molecular Biomedical Research (DMBR), VIB-Ghent University,
Technologiepark 927 B-9052, Ghent (Zwijnaarde), Belgium.
JASPAR is the most complete open-access collection of transcription factor
binding site (TFBS) matrices. In this new release, JASPAR grows into a
meta-database of collections of TFBS models derived by diverse approaches. We
present JASPAR CORE--an expanded version of the original, non-redundant
collection of annotated, high-quality matrix-based transcription factor binding
profiles, JASPAR FAM--a collection of familial TFBS models and JASPAR
phyloFACTS--a set of matrices computationally derived from statistically
overrepresented, evolutionarily conserved regulatory region motifs from
mammalian genomes. JASPAR phyloFACTS serves as a non-redundant extension to
JASPAR CORE, enhancing the overall breadth of JASPAR for promoter sequence
analysis. The new release of JASPAR is available at http://jaspar.genereg.net.
DOI: 10.1093/nar/gkj115
PMCID: PMC1347477
PMID: 16381983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21816077 | 1. Crit Care. 2011 Aug 4;15(4):R186. doi: 10.1186/cc10339.
Urine hepcidin has additive value in ruling out cardiopulmonary
bypass-associated acute kidney injury: an observational cohort study.
Haase-Fielitz A(1), Mertens PR, Plass M, Kuppe H, Hetzer R, Westerman M, Ostland
V, Prowle JR, Bellomo R, Haase M.
Author information:
(1)Department of Nephrology and Hypertension & Endocrinology and Metabolic
Diseases, Otto-von-Guericke-University, Leipziger Strasse 44, D-39120 Magdeburg,
Germany.
INTRODUCTION: Conventional markers of acute kidney injury (AKI) lack diagnostic
accuracy and are expressed only late after cardiac surgery with cardiopulmonary
bypass (CPB). Recently, interest has focused on hepcidin, a regulator of iron
homeostasis, as a unique renal biomarker.
METHODS: We studied 100 adult patients in the control arm of a randomized,
controlled trial http://www.clinicaltrials.gov/NCT00672334 who were identified
as being at increased risk of AKI after cardiac surgery with CPB. AKI was
defined according to the Risk, Injury, Failure, Loss, End-stage renal disease
classification of AKI classification stage. Samples of plasma and urine were
obtained simultaneously (1) before CPB (2) six hours after the start of CPB and
(3) twenty-four hours after CPB. Plasma and urine hepcidin 25-isoforms were
quantified by competitive enzyme-linked immunoassay.
RESULTS: In AKI-free patients (N = 91), urine hepcidin concentrations had
largely increased at six and twenty-four hours after CPB, and they were three to
seven times higher compared to patients with subsequent AKI (N = 9) in whom
postoperative urine hepcidin remained at preoperative levels (P = 0.004, P =
0.002). Furthermore, higher urine hepcidin and, even more so, urine hepcidin
adjusted to urine creatinine at six hours after CPB discriminated patients who
did not develop AKI (area under the curve (AUC) receiver operating
characteristic curve 0.80 [95% confidence interval (95% CI) 0.71 to 0.87] and
0.88 [95% CI 0.78 to 0.97]) or did not need renal replacement therapy initiation
(AUC 0.81 [95% CI 0.72 to 0.88] 0.88 [95% CI 0.70 to 0.99]) from those who did.
At six hours, urine hepcidin adjusted to urine creatinine was an independent
predictor of ruling out AKI (P = 0.011). Plasma hepcidin did not predict no
development of AKI. The study findings remained essentially unchanged after
excluding patients with preoperative chronic kidney disease.
CONCLUSIONS: Our findings suggest that urine hepcidin is an early predictive
biomarker of ruling out AKI after CPB, thereby contributing to early patient
risk stratification.
DOI: 10.1186/cc10339
PMCID: PMC3387629
PMID: 21816077 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16426878 | 1. Eur J Pain. 2006 Nov;10(8):701-9. doi: 10.1016/j.ejpain.2005.11.004. Epub 2006
Jan 19.
The relationship between activity and pain in patients 6 months after lumbar
disc surgery: do pain-related coping modes act as moderator variables?
Hasenbring MI(1), Plaas H, Fischbein B, Willburger R.
Author information:
(1)Ruhr-University of Bochum, Faculty of Medicine, Department of Medical
Psychology and Medical Sociology, 44780 Bochum, NRW, Germany.
BACKGROUND: In LBP patients, the relationship between pain and physical activity
remains unclear. Whereas a negative relationship between pain and self-reported
physical activity was found, this relation disappeared in the case of overt
behavioral data (e.g., accelerometer). Cognitive-behavioral models of the
development of chronic pain suggest subgroups with signs of physical underuse
and overuse.
AIMS: To examine if patients with pain-related adaptive, endurance and
fear-avoidance coping differ in pain, self-reported physical function and overt
physical activity 6 months after disc surgery.
METHODS: 24 patients completed questionnaires (Von Korff chronic pain grade
(CPG), Kiel pain inventory (KPI), Funktionsfragebogen Hannover-Rücken FFbH-R)
and underwent an 8-h accelerometer assessment in their daily life (physical
activity level (PAL), number of constant postures (CP)). The KPI differed
between adaptive coping (AC) (N=9), fear avoidance coping (FAC) (N=1) and
endurance coping (EC) (N=14).
RESULTS: In the whole group, pain intensity was negative related to
self-reported physical activity whereas PAL and CP displayed no correlation with
pain. EC patients showed significantly higher pain scores and lower
self-reported physical functioning compared to AC but the same level of PAL and
furthermore, a significantly higher number of CPs in daily life. The visual
inspection of the FAC patient revealed also high pain, low physical functioning
and low overt physical activity.
CONCLUSIONS: The assessment of pain-related coping modes yielded an important
differentiation between subgroups of LBP patients 6 months after surgery.
Endurance copers displayed signs of overuse in their daily behavior in spite of
pain than adaptive copers. The one fear avoidance coper tends to do less
physical activity in the sense of underuse.
DOI: 10.1016/j.ejpain.2005.11.004
PMID: 16426878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24133923 | 1. Clin Lab. 2013;59(7-8):909-13.
Concentration of plasma neutrophil gelatinase-associated lipocalin in patients
with chronic kidney disease.
Wu KD(1), Hsing LL, Huang YF.
Author information:
(1)Department of Clinical Laboratory, Pingtung Christian Hospital, Taiwan.
BACKGROUND: The inclining incidence of chronic kidney disease which has led to
high mortality and immense medical burden over the past decades has become a
distressing concern in epidemiology. Unfortunately, the number of biomarkers
that allow the monitoring of chronic kidney disease (CKD) is limited. Neutrophil
gelatinase-associated lipocalin (NGAL) is an emerging biomarker which has been
shown to be able to diagnose kidney injuries.
METHODS: Eighty-one nondiabetic patients with chronic kidney disease, stage 2 to
5, were recruited for this study, and 17 healthy volunteers with eGFR greater
than 90 mL/minute/1.73m(2) were selected as the control group.
RESULTS: Our study demonstrated that the pNGAL level is elevated during CKD, and
the pNGL level has a strong correlation with the concentration of sCr and eGFR.
CONCLUSIONS: Plasma neutrophil gelatinase-associated lipocalin is a potent tool
in the diagnosis of chronic kidney diseases and is shown to have high
correlation with serum creatinine and estimated glomerular filtration rate.
PMID: 24133923 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16437292 | 1. J Clin Monit Comput. 2005 Dec;19(6):411-4. doi: 10.1007/s10877-005-0392-8.
Epub 2006 Jan 25.
Analysis of nighttime activity and daytime pain in patients with chronic back
pain using a self-organizing map neural network.
Liszka-Hackzell JJ(1), Martin DP.
Author information:
(1)Department of Anesthesiology, University of Arizona, 1501 N. Campbell Ave.,
Tucson, 85724, USA. [email protected]
There may be a relationship between sleep and pain in patients with chronic back
pain. We collected day-time pain and nighttime activity data from 18 patients
diagnosed with chronic back pain. The patients were followed for 6 days and 5
nights. Pain levels were collected every 90 min between 0800 hours and 2,200
hours using a computerized electronic diary. Activity levels were collected
using a wrist accelerometer (Actiwatch AW-64). The Actiwatch sampled activity
counts every 1 min. Patients were asked to wear the Actiwatch on their
non-dominant arm. The pain level measurements were interpolated using cubic
splines. A mean pain level was calculated for each period 0800 hours to 2,200
hours as well as for the 6-day period. The difference between the mean pain
levels for the 6-day period and each 0800 hours to 2,200 hours period was
calculated for each patient. Nighttime activity data were analyzed using the
Actiwatch Sleep Analysis software. Correlations were calculated between the
Actiwatch Sleep Analysis variables and the mean pain level differences for each
patient and period. The correlation analysis was performed with SPSS 7.5. We
were unable to show any significant relationships.A different approach to
analyze the data was used. A Self-Organizing Map (SOM) Neural Network was
trained using the original nighttime activity level time series from 10 randomly
selected patients. Recall was then performed on all the activity level data.
Correlations were calculated between the pain level variance for the 6-day
period for each patient and the corresponding difference in the SOM output
coordinates. The correlation was found to be r = 0.73, p < 0.01). We conclude
that daytime pain levels are not directly correlated with sleep in the following
night and that sleep is not directly correlated with daytime pain levels on the
following day in this group of patients. There appears to be a correlation
between the difference in nighttime activity levels and patterns and the daytime
pain variance. Patients who experience large fluctuations in daytime pain levels
also show a higher variability in their nighttime activity levels and patterns.
Even though we were unable to show a direct relationship between daytime pain
and sleep, it may be reasonable to assume that better pain control resulting in
less daytime pain fluctuations can provide more stable nighttime activity levels
and patterns in this limited group of patients. By using a neural network model,
we were able to extract information from the nighttime activity levels even
though a traditional statistical analysis was unsuccessful.
DOI: 10.1007/s10877-005-0392-8
PMID: 16437292 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19945891 | 1. Eur J Pain. 2010 Jul;14(6):661-6. doi: 10.1016/j.ejpain.2009.10.014. Epub 2009
Nov 28.
Is physical functioning influenced by activity-related pain prediction and fear
of movement in patients with subacute low back pain?
Huijnen IP(1), Verbunt JA, Peters ML, Seelen HA.
Author information:
(1)Department of Rehabilitation Medicine, Research School CAPHRI, Maastricht
University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
[email protected]
In patients with low back pain (LBP), physical functioning may be negatively
influenced by both expectations on pain and pain-related fear. It is unclear
whether these factors influence both physical functioning in the laboratory as
well as in daily life. The aim of this study was to test if a combination of
persistent overprediction of pain and fear of movement predicts lab-based
performance and whether these factors are relevant for predicting daily-life
functioning. One hundred and twenty four patients with subacute LBP performed a
laboratory-based performance test twice. Maximum voluntary contraction, pre-test
pain expectations, perceived pain during testing and fear of movement were
measured. Patients were classified as correct or incorrect predictors, based on
differences between expected and perceived pain on the second attempt. Next,
physical activity in daily life was measured with an accelerometer. In
explaining physical functioning in the laboratory and in daily life an
interaction effect between fear and pain prediction was observed. In
overpredictors, fear was negatively associated with lab-based performance
(beta=-0.48, p<0.01), and positively associated with daily-life functioning
(beta=0.50, p<0.05). No significant association between fear and performance or
daily-life functioning were found in correct predictors. In contrast to correct
predictors, in overpredictors lab-based performance and daily-life functioning
was additionally explained by fear of movement. Thus it appears that fear of
movement is only predictive of performance in patients with LBP who
simultaneously overpredict the consequences of movements in terms of
painfulness.
Copyright (c) 2009 European Federation of International Association for the
Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ejpain.2009.10.014
PMID: 19945891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21099121 | 1. Circ J. 2011;75(1):99-105. doi: 10.1253/circj.cj-10-0525. Epub 2010 Nov 16.
Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after
drug-eluting stent implantation in Japanese patients receiving clopidogrel.
Sawada T(1), Shinke T, Shite J, Honjo T, Haraguchi Y, Nishio R, Shinohara M, Toh
R, Ishida T, Kawamori H, Kozuki A, Inoue T, Hariki H, Hirata K.
Author information:
(1)Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe
University Graduate School of Medicine, Kobe, Japan.
BACKGROUND: The cytochrome P450 (CYP) 2C19*2 polymorphism is associated with
reduced responsiveness to clopidogrel and poor clinical outcome after stent
implantation. Despite the high frequency of this polymorphism in Japanese
patients, its contribution to cardiac events and stent thrombi after
drug-eluting stent (DES) implantation is not clear in this population.
METHODS AND RESULTS: One hundred Japanese patients received clopidogrel and
underwent follow-up optical coherence tomography (OCT) after DES implantation.
The patients were divided into 2 groups: those with at least one CYP2C19*2
allele (*2 carriers) and non-carriers. The incidence of stent thrombosis and
major adverse cardiac events (MACE; ie, death, myocardial infarction, and target
vessel revascularization) was compared between the 2 groups. In addition, OCT
was used to evaluate the incidence of intra-stent thrombus, defined as a mass
protruding into the lumen with significant attenuation. Of the 100 patients, 42
were *2 carriers. No remarkable differences in the baseline characteristics were
noted. Although MACE did not differ significantly between the 2 groups, a
subclinical intra-stent thrombus was detected more frequently in *2 carriers
than in non-carriers (52.3% vs. 15.5%, P=0.0002). Multivariate logistic
regression analysis showed that the presence of the CYP2C19*2 polymorphism was
the only independent predictive factor for intra-stent thrombus (P=0.00006).
CONCLUSIONS: From these results it is suggested that CYP2C19*2 polymorphism is
associated with subclinical thrombus formation among Japanese patients receiving
clopidogrel. (Circ J 2011; 75: 99-105).
DOI: 10.1253/circj.cj-10-0525
PMID: 21099121 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19463375 | 1. JACC Cardiovasc Interv. 2008 Dec;1(6):620-7. doi: 10.1016/j.jcin.2008.09.008.
The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis
from the PRINC (Plavix Response in Coronary Intervention) trial.
Gladding P(1), Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J,
El-Jack S, Armstrong G, Kay P, Scott D, Gunes A, Dahl ML.
Author information:
(1)Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New
Zealand. [email protected]
Comment in
JACC Cardiovasc Interv. 2008 Dec;1(6):628-30. doi:
10.1016/j.jcin.2008.10.002.
OBJECTIVES: This study assessed the effect of pharmacogenetics on the
antiplatelet effect of clopidogrel.
BACKGROUND: Variability in clopidogrel response might be influenced by
polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP]
family), transport proteins (P-glycoprotein) and/or target proteins for the drug
(adenosine diphosphate-receptor P2Y12).
METHODS: Sixty patients undergoing elective percutaneous coronary intervention
in the randomized PRINC (Plavix Response in Coronary Intervention) trial had
platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or
split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage.
Polymerase chain reaction-based genotyping evaluated polymorphisms in the
CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.
RESULTS: CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg
dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in
CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers
(9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet
inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8%
to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher
maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).
CONCLUSIONS: Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet
inhibition after a clopidogrel 600-mg loading dose but responded to higher
loading and maintenance dose regimens. Genotyping for the relevant gene
polymorphisms may help to individualize and optimize clopidogrel treatment.
(Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).
DOI: 10.1016/j.jcin.2008.09.008
PMID: 19463375 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24205707 | 1. Rinsho Byori. 2013 Jul;61(7):635-40.
[Urinary L-type fatty acid binding protein (L-FABP) as a new urinary biomarker
promulgated by the Ministry of Health, Labour and Welfare in Japan].
[Article in Japanese]
Kamijo-Ikemori A(1), Ichikawa D, Matsui K, Yokoyama T, Sugaya T, Kimura K.
Author information:
(1)Department of Nephrology and Hypertension, St. Marianna University School of
Medicine, Kawasaki 261-8511, Japan.
Liver-type fatty acid binding protein (L-FABP) is a 14kDa protein found in the
cytoplasm of human renal proximal tubules. Fatty acids are bound with L-FABP and
transported to the mitochondria or peroxisomes, where fatty acids are
beta-oxidized, and this may play a role in fatty acid homeostasis. Moreover,
L-FABP has high affinity and capacity to bind long-chain fatty acid oxidation
products, and may be an effective endogenous antioxidant. Renal L-FABP is rarely
expressed in the kidneys of rodents. In order to evaluate the pathological
dynamics of renal L-FABP in kidney disease, human L-FABP chromosomal transgenic
mice were generated. Various stress, such as massive proteinuria, hyperglycemia,
hypertension, and toxins overloaded in the proximal tubules were revealed to
up-regulate the gene expression of renal L-FABP and increase the excretion of
L-FABP derived from the proximal tubules into urine. In clinical studies of
chronic kidney disease (CKD), urinary L-FABP accurately reflected the degree of
tubulointerstitial damage and correlated with the rate of CKD progression.
Furthermore, a multicenter trial has shown that urinary L-FABP is more sensitive
than urinary protein in predicting the progression of CKD. With respect to
diabetic nephropathy and acute kidney disease (AKI), urinary L-FABP is an early
diagnostic of kidney disease or a predictive marker for renal prognosis. After
many clinical studies, urinary L-FABP was approved as a new tubular biomarker
promulgated by the Ministry of Health, Labour and Welfare in Japan.
PMID: 24205707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21886760 | 1. J Dermatol Case Rep. 2011 Mar 26;5(1):14-6. doi: 10.3315/jdcr.2011.1064.
Photoletter to the editor: A new variant of ichthyosis follicularis with
alopecia and photophobia (IFAP) syndrome with coexisting psoriasiform lesions
and palmoplantar keratoderma. IFAP-PPK syndrome?
Alshami M(1), Bawazir MA, Atwan AA.
Author information:
(1)Department of Dermatology, Kuwait University Hospital, Sana'a University,
P.O. Box 1950, Sana'a, Yemen.
IFAP is an acronym for a rare congenital ectodermal disorder characterized by
ichthyosis follicularis, alopecia and photophobia. A recessive X-linked mode of
inheritance was initially proposed but recent reports in girls suggested genetic
heterogeneity of this syndrome. We herein describe a 1-year-old boy with
clinical features typical of IFAP syndrome plus psoriasis-like lesions and
palmoplantar keratoderma (PPK).
DOI: 10.3315/jdcr.2011.1064
PMCID: PMC3163350
PMID: 21886760 |
http://www.ncbi.nlm.nih.gov/pubmed/10398262 | 1. Am J Med Genet. 1999 Aug 6;85(4):365-8. doi:
10.1002/(sici)1096-8628(19990806)85:4<365::aid-ajmg12>3.0.co;2-#.
Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome
(ichthyosis follicularis with atrichia and photophobia).
König A(1), Happle R.
Author information:
(1)Department of Dermatology, Philipp University, Marburg, Germany.
A diagnosis of IFAP (ichthyosis follicularis with atrichia and photophobia)
syndrome was established in a 1-year-old boy with congenital hairlessness,
generalized ichthyotic skin changes with follicular hyperkeratoses, and
photophobia. IFAP syndrome is considered to be an X-linked recessive trait. The
phenotype present in female carriers has so far not been delineated. A
2-year-old sister had atrophoderma and ichthyotic skin lesions arranged in a
linear pattern and a large noncicatrical bald patch on her scalp. Similarly, the
mother had linear lesions of scaling and atrophy as well as circumscribed
hairless areas involving the scalp, the axillary region, and the lower legs.
Sweat testing by means of iodine starch-reaction visualized hypohidrotic linear
lesions corresponding to the areas of hyperkeratosis and atrophy. In both mother
and daughter the lesions followed the lines of Blaschko, whereas the boy was
diffusely affected. Family history showed that the boy's maternal uncle who had
died at age 1 year was likewise affected with the same disorder. Moreover, the
maternal grandmother had reportedly bald patches on her scalp and very dry skin.
This is the first report to document linear skin lesions visualizing lyonization
in women heterozygous for IFAP syndrome.
Copyright 1999 Wiley-Liss, Inc.
DOI: 10.1002/(sici)1096-8628(19990806)85:4<365::aid-ajmg12>3.0.co;2-#
PMID: 10398262 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18006571 | 1. Nucleic Acids Res. 2008 Jan;36(Database issue):D102-6. doi:
10.1093/nar/gkm955. Epub 2007 Nov 15.
JASPAR, the open access database of transcription factor-binding profiles: new
content and tools in the 2008 update.
Bryne JC(1), Valen E, Tang MH, Marstrand T, Winther O, da Piedade I, Krogh A,
Lenhard B, Sandelin A.
Author information:
(1)Computational Biology Unit, Bergen Center for Computational Science,
University of Bergen, Thormøhlensgate 55, N-5008 Bergen, Norway.
JASPAR is a popular open-access database for matrix models describing
DNA-binding preferences for transcription factors and other DNA patterns. With
its third major release, JASPAR has been expanded and equipped with additional
functions aimed at both casual and power users. The heart of the JASPAR
database-the JASPAR CORE sub-database-has increased by 12% in size, and three
new specialized sub-databases have been added. New functions include clustering
of matrix models by similarity, generation of random matrices by sampling from
selected sets of existing models and a language-independent Web Service
applications programming interface for matrix retrieval. JASPAR is available at
http://jaspar.genereg.net.
DOI: 10.1093/nar/gkm955
PMCID: PMC2238834
PMID: 18006571 [Indexed for MEDLINE] |