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http://www.ncbi.nlm.nih.gov/pubmed/25239977 | 1. Eukaryot Cell. 2014 Nov;13(11):1465-9. doi: 10.1128/EC.00213-14. Epub 2014 Sep
19.
Successful transient expression of Cas9 and single guide RNA genes in
Chlamydomonas reinhardtii.
Jiang W(1), Brueggeman AJ(1), Horken KM(1), Plucinak TM(1), Weeks DP(2).
Author information:
(1)Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA.
(2)Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
[email protected].
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9
system has become a powerful and precise tool for targeted gene modification
(e.g., gene knockout and gene replacement) in numerous eukaryotic organisms.
Initial attempts to apply this technology to a model, the single-cell alga,
Chlamydomonas reinhardtii, failed to yield cells containing edited genes. To
determine if the Cas9 and single guide RNA (sgRNA) genes were functional in C.
reinhardtii, we tested the ability of a codon-optimized Cas9 gene along with one
of four different sgRNAs to cause targeted gene disruption during a 24-h period
immediately following transformation. All three exogenously supplied gene
targets as well as the endogenous FKB12 (rapamycin sensitivity) gene of C.
reinhardtii displayed distinct Cas9/sgRNA-mediated target site modifications as
determined by DNA sequencing of cloned PCR amplicons of the target site region.
Success in transient expression of Cas9 and sgRNA genes contrasted with the
recovery of only a single rapamycin-resistant colony bearing an appropriately
modified FKB12 target site in 16 independent transformation experiments
involving >10(9) cells. Failure to recover transformants with intact or
expressed Cas9 genes following transformation with the Cas9 gene alone (or even
with a gene encoding a Cas9 lacking nuclease activity) provided strong
suggestive evidence for Cas9 toxicity when Cas9 is produced constitutively in C.
reinhardtii. The present results provide compelling evidence that Cas9 and sgRNA
genes function properly in C. reinhardtii to cause targeted gene modifications
and point to the need for a focus on development of methods to properly stem
Cas9 production and/or activity following gene editing.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
DOI: 10.1128/EC.00213-14
PMCID: PMC4248704
PMID: 25239977 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15073377 | 1. Science. 2004 Apr 9;304(5668):292-6. doi: 10.1126/science.1094301.
Protection from cardiac arrhythmia through ryanodine receptor-stabilizing
protein calstabin2.
Wehrens XH(1), Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas
J, Landry DW, Marks AR.
Author information:
(1)Department of Physiology and Cellular Biophysics, Columbia University College
of Physicians and Surgeons, New York, NY 10032, USA.
Comment in
Expert Opin Ther Targets. 2004 Dec;8(6):663-5. doi:
10.1517/14728222.8.6.663.
Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with
normal hearts and in those with underlying disease such as heart failure. In
animals with heart failure and in patients with inherited forms of
exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2
(FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex
causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A
derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2
for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak
that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may
be a therapeutic strategy for common ventricular arrhythmias.
DOI: 10.1126/science.1094301
PMID: 15073377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22088988 | 1. J Thorac Oncol. 2011 Dec;6(12):1984-92. doi: 10.1097/JTO.0b013e3182307eac.
The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung
cancer and induces migration and tumor growth.
Schmidt LH(1), Spieker T, Koschmieder S, Schäffers S, Humberg J, Jungen D, Bulk
E, Hascher A, Wittmer D, Marra A, Hillejan L, Wiebe K, Berdel WE, Wiewrodt R,
Muller-Tidow C.
Author information:
(1)Department of Medicine A, Hematology, Oncology and Pulmonary Medicine,
University Hospital Muenster, Muenster, Germany.
Erratum in
J Thorac Oncol. 2012 Jul;7(7):1206. Schäffers, Sonja [added].
INTRODUCTION: The functions of large noncoding RNAs (ncRNAs) have remained
elusive in many cases. Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1
(MALAT-1) is an ncRNA that is highly expressed in several tumor types.
METHODS: Overexpression and RNA interference (RNAi) approaches were used for the
analysis of the biological functions of MALAT-1 RNA. Tumor growth was studied in
nude mice. For prognostic analysis, MALAT-1 RNA was detected on
paraffin-embedded non-small cell lung cancer (NSCLC) tissue probes (n = 352)
using in situ hybridization.
RESULTS: MALAT-1 was highly expressed in several human NSCLC cell lines. MALAT-1
expression was regulated by an endogenous negative feedback loop. In A549
NSCLCs, RNAi-mediated suppression of MALAT-1 RNA suppressed migration and
clonogenic growth. Forced expression of MALAT-1 in NIH 3T3 cells significantly
increased migration. Upon injection into nude mice, NSCLC xenografts with
decreased MALAT-1 expression were impaired in tumor formation and growth. In
situ hybridization on paraffin-embedded lung cancer tissue probes revealed that
high MALAT-1 RNA expression in squamous cell carcinoma of the lung was
associated with a poor prognosis. On genetic level, MALAT-1 displays the
strongest association with genes involved in cancer like cellular growth,
movement, proliferation, signaling, and immune regulation.
CONCLUSIONS: These data indicate that MALAT-1 expression levels are associated
with patient survival and identify tumor-promoting functions of MALAT-1.
DOI: 10.1097/JTO.0b013e3182307eac
PMID: 22088988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20877344 | 1. Mol Ther. 2011 Feb;19(2):408-16. doi: 10.1038/mt.2010.201. Epub 2010 Sep 28.
Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of
Netherton syndrome-derived skin grafts.
Di WL(1), Larcher F, Semenova E, Talbot GE, Harper JI, Del Rio M, Thrasher AJ,
Qasim W.
Author information:
(1)Department of Immunobiology, UCL Institute of Child Health, London, UK.
Netherton syndrome (NS) is a debilitating congenital skin disorder caused by
mutations in the SPINK5 gene encoding the lymphoepithelial Kazal-type-related
inhibitor (LEKTI). It is characterized by defective keratinization, recurrent
infections, and hypernatraemic dehydration with a mortality rate of about 10% in
the first year of life. Currently, there are no curative treatments for NS. We
have developed a HIV-1 based, self-inactivating lentiviral vector to express
SPINK5 in keratinocytes as part of an ex-vivo gene therapy strategy for NS. High
transduction efficiency was achieved in NS keratinocytes and reconstitution of
LEKTI expression was confirmed in previously deficient cells. These genetically
corrected keratinocytes were further tested in an in vitro organotypic culture
(OTC) system and in vivo mouse/human skin engraftment model. Results showed
correction of epidermal architecture in both OTCs and regenerated skin grafts.
Importantly, the results from corrected skin grafts indicated that even where
detectable LEKTI expression was restored to a limited numbers of cells, a wider
bystander benefit occurred around these small populations. As LEKTI is a
secreted protein, the genetically modified graft may provide not only an
immediate local protective barrier, but also act as a source of secreted LEKTI
providing a generalized benefit following ex-vivo gene therapy.
DOI: 10.1038/mt.2010.201
PMCID: PMC3034839
PMID: 20877344 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11841556 | 1. J Invest Dermatol. 2002 Feb;118(2):352-61. doi:
10.1046/j.1523-1747.2002.01603.x.
Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21
families.
Bitoun E(1), Chavanas S, Irvine AD, Lonie L, Bodemer C, Paradisi M,
Hamel-Teillac D, Ansai S, Mitsuhashi Y, Taïeb A, de Prost Y, Zambruno G, Harper
JI, Hovnanian A.
Author information:
(1)Wellcome Trust Center for Human Genetics, Oxford, UK.
Netherton syndrome is a severe autosomal recessive skin disorder characterized
by congenital erythroderma, a specific hair-shaft abnormality, and atopic
manifestations with high IgE levels. Recently, we identified SPINK5, which
encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the
defective gene in Netherton syndrome. Here we describe the intron-exon
organization of the gene and characterize the SPINK5 mutations in patients from
21 families of different geographic origin, using denaturing high performance
liquid chromatography and direct sequencing. We identified 18 mutations, of
which 13 were novel and seven (39%) were recurrent. The majority of the
mutations were clustered between exons 1-8 and exons 21-26. They comprised four
nonsense mutations (22%), eight frameshift insertions or deletions (44%), and
six splice-site defects (33%). All mutations predict the formation of premature
termination codons. Northern blot analysis showed variable reduction of SPINK5
mutant transcript levels, suggesting variable efficiency of nonsense-mediated
mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes,
and five were heterozygotes with only one identifiable SPINK5 mutation. Five
mutations, one of which resulted in perinatal lethal disease in three families,
were associated with certain ethnic groups. We also describe 45 intragenic
polymorphisms in the patients studied. The clinical features of erythroderma,
trichorrhexis invaginata, and atopic manifestations were present in the majority
of affected individuals and ichthyosis linearis circumflexa was seen in 12 out
of 24 patients. Interfamilial and intrafamilial variation in disease severity
was observed, with no clear correlation between mutations and phenotype,
suggesting that the degree of severity may be affected by other factors.
DOI: 10.1046/j.1523-1747.2002.01603.x
PMID: 11841556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23471993 | 1. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4691-6. doi:
10.1073/pnas.1220865110. Epub 2013 Mar 7.
Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2
(Th2) cell identity.
Hosokawa H(1), Tanaka T, Suzuki Y, Iwamura C, Ohkubo S, Endoh K, Kato M, Endo Y,
Onodera A, Tumes DJ, Kanai A, Sugano S, Nakayama T.
Author information:
(1)Department of Immunology, Graduate School of Medicine, Chiba University,
Chiba 260-8670, Japan.
GATA binding protein 3 (Gata3) is a GATA family transcription factor that
controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells.
However, it is unknown how Gata3 simultaneously activates Th2-specific genes
while repressing those of other Th lineages. Here we show that chromodomain
helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells
that both activates Th2 cytokine transcription and represses the Th1 cytokine
IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2
cytokine loci and a Gata3/Chd4-nucleosome remodeling histone deacetylase
repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a
physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of
asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes,
which mediate both positive and negative gene regulation to facilitate Th2 cell
differentiation.
DOI: 10.1073/pnas.1220865110
PMCID: PMC3606997
PMID: 23471993 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23104528 | 1. |
http://www.ncbi.nlm.nih.gov/pubmed/25486928 | 1. Blood Cells Mol Dis. 2015 Feb;54(2):155-9. doi: 10.1016/j.bcmd.2014.11.016.
Epub 2014 Nov 26.
Modulation of pain in pediatric sickle cell disease: understanding the balance
between endothelin mediated vasoconstriction and apelin mediated vasodilation.
Smith TP(1), Schlenz AM(2), Schatz JC(2), Maitra R(3), Sweitzer SM(4).
Author information:
(1)Department of Pharmacology, Physiology and Neuroscience, University of South
Carolina, Columbia, SC, USA. Electronic address: [email protected].
(2)Department of Psychology, University of South Carolina, Columbia, SC, USA.
(3)RTI International, Research Triangle Park, NC, USA.
(4)Department of Pharmacology, Physiology and Neuroscience, University of South
Carolina, Columbia, SC, USA; Department of Pharmaceutical and Administrative
Sciences, Presbyterian College School of Pharmacy, Clinton, SC, USA.
Children with sickle cell disease (SCD) have painful vaso-occlusive episodes
(VOEs), which often reoccur across the individual's lifespan. Vaso-constrictive
and vaso-dilatory molecules have been hypothesized to play a role in VOEs.
Endothelin-1 (ET-1) is a potent vasoconstrictor that is released during VOEs and
is correlated with pain history. Apelin is a vaso-dilatory peptide that also has
a modulatory role in pain processing. We hypothesize that the ratio between
vaso-dilatory and vaso-constrictive tone in children with SCD may be a marker of
pain sensitization and vaso-occlusion. Plasma endothelin and apelin levels were
measured in 47 children with SCD. Procedural pain and baseline pain were
assessed via child- and caregiver-reports and observational distress. Pain
history was assessed using retrospective chart review. Plasma apelin was related
to age, with decreased levels in older children. The ratio between apelin and
ET-1 was negatively correlated to observational baseline pain. The ratio between
apelin and Big ET was negatively correlated to caregiver ratings of baseline
pain and positively correlated to history of VOEs, which is possibly due to
hydroxyurea treatment. These results suggest that an imbalance in the apelin and
endothelin systems may contribute to an increasing number of VOEs and baseline
pain in children with SCD.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bcmd.2014.11.016
PMCID: PMC4297528
PMID: 25486928 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25005481 | 1. Clin Orthop Relat Res. 2014 Oct;472(10):3216-25. doi:
10.1007/s11999-014-3766-8. Epub 2014 Jul 9.
Are copy number variants associated with adolescent idiopathic scoliosis?
Buchan JG(1), Alvarado DM, Haller G, Aferol H, Miller NH, Dobbs MB, Gurnett CA.
Author information:
(1)Department of Genetics, Washington University School of Medicine, 660 S
Euclid Ave, Box 8111, St. Louis, MO, 63110, USA.
Comment in
Clin Orthop Relat Res. 2014 Oct;472(10):3226-7. doi:
10.1007/s11999-014-3807-3.
BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder
that causes spinal deformity in approximately 3% of the population. Candidate
gene, linkage, and genome-wide association studies have sought to identify
genetic variation that predisposes individuals to AIS, but the genetic basis
remains unclear. Copy number variants are associated with several isolated
skeletal phenotypes, but their role in AIS, to our knowledge, has not been
assessed.
QUESTIONS/PURPOSES: We determined the frequency of recurrent copy number
rearrangements, chromosome aneuploidy, and rare copy number variants in patients
with AIS.
METHODS: Between January 2010 and August 2014, we evaluated 150 patients with
isolated AIS and spinal curvatures measuring 10° or greater, and 148 agreed to
participate. Genomic copy number analysis was performed on patients and 1079
control subjects using the Affymetrix(®) Genome-wide Human SNP Array 6.0. After
removing poor quality samples, 143 (97%) patients with AIS were evaluated for
copy number variation.
RESULTS: We identified a duplication of chromosome 1q21.1 in 2.1% (N = 3/143) of
patients with AIS, which was enriched compared with 0.09% (N = 1/1079) of
control subjects (p = 0.0057) and 0.07% (N = 6/8329) of a large published
control cohort (p = 0.0004). Other notable findings include trisomy X, which was
identified in 1.8% (N = 2/114) of female patients with AIS, and rearrangements
of chromosome 15q11.2 and 16p11.2 that previously have been associated with
spinal phenotypes. Finally, we report rare copy number variants that will be
useful in future studies investigating candidate genes for AIS.
CONCLUSIONS: Copy number variation and chromosomal aneuploidy may contribute to
the pathogenesis of adolescent idiopathic scoliosis.
CLINICAL RELEVANCE: Chromosomal microarray may reveal clinically useful
abnormalities in some patients with AIS.
DOI: 10.1007/s11999-014-3766-8
PMCID: PMC4160470
PMID: 25005481 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16307658 | 1. Br J Dermatol. 2005 Dec;153(6):1200-3. doi: 10.1111/j.1365-2133.2005.06834.x.
hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by
LEKTI domain 6.
Egelrud T(1), Brattsand M, Kreutzmann P, Walden M, Vitzithum K, Marx UC,
Forssmann WG, Mägert HJ.
Author information:
(1)Department of Public Health and Clinical Medicine, Dermatology and
Venereology, University of Umeå, Umeå, Sweden.
BACKGROUND: Several skin diseases and atopic disorders including Netherton
syndrome and atopic dermatitis have been associated with mutations and
deviations of expression of SPINK5, the gene encoding the human 15-domain serine
proteinase inhibitor LEKTI. The biochemical mechanisms underlying this
phenomenon have not yet been fully clarified.
OBJECTIVES: To identify target proteinases of LEKTI important for processes of
desquamation and inflammation of the skin which will enable the development of
specific drugs.
METHODS: The inhibitory activities of LEKTI domains 6 and 15 were tested on a
number of commercially available serine proteinases and also on the purified
kallikreins hK5 and hK7. In addition, recombinant hK5 was used.
RESULTS: LEKTI domain 6 is a potent inhibitor of hK5 and hK7, whereas LEKTI
domain 15 exhibits inhibitory activity on plasmin. hK5 and hK7 in particular are
relevant to skin disorders.
CONCLUSIONS: The inhibition of hK5 and hK7 by LEKTI domain 6 indicates an
important regulatory role of LEKTI in processes of skin desquamation and
inflammation, which may explain the severe pathological symptoms associated with
abnormalities of SPINK5 and/or its expression. Thus, LEKTI represents a
potential drug for the treatment of these disorders.
DOI: 10.1111/j.1365-2133.2005.06834.x
PMID: 16307658 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21251800 | 1. J Dermatol Sci. 2011 Mar;61(3):194-8. doi: 10.1016/j.jdermsci.2010.12.004.
Epub 2010 Dec 21.
rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton
patients.
Roedl D(1), Oji V, Buters JT, Behrendt H, Braun-Falco M.
Author information:
(1)Division of Environmental Dermatology and Allergy, ZAUM Center for Allergy
and Environment, Technische Universität München, Munich, Germany.
BACKGROUND: Netherton syndrome (NS, MIM 256500) is a potential live threatening
autosomal-recessive skin disorder clinically characterized by the trias of
congenital erythroderma, hair shaft anomalies and atopic diathesis. It is caused
by mutations in the gene SPINK5 resulting in a deficiency of its processed
protein named lympho-epithelial Kazal-type related inhibitor (LEKTI). LEKTI
controls the activity of several serine proteases in the skin that are involved
in terminal differentiation. Loss of LEKTI results in protease hyperactivity,
increased degradation of intercellular junctions, reduced stratum corneum
adhesion and impaired skin barrier function. Today NS can only be treated
symptomatically.
OBJECTIVE: Does gene transfer offer a therapeutic option for NS in the future?
METHODS: A recombinant adeno-associated virus type 2 vector was constructed
containing the full length cDNA (rAAV2/C-SPINK5) of functional human LEKTI.
Infectious virus particles were used for transfection of
LEKTI-deficient-keratinocytes of NS patients in vitro.
RESULTS: Gene transfer of SPINK5 in NS-keratinocytes led to a five-fold increase
in mRNA expression of SPINK5 reaching almost 75% of normal value. The
functionality of the expressed LEKTI was proven in a hydrolytic activity assay
demonstrating that the activity of LEKTI after gene transfer increased closely
to the level seen in keratinocytes of healthy individuals.
CONCLUSION: The results provide first evidence that gene transfer of SPINK5
results in increased LEKTI activity in NS-keratinocytes, thus offering a
rational to further pursue such a gene therapy approach for NS.
Copyright © 2010 Japanese Society for Investigative Dermatology. Published by
Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.jdermsci.2010.12.004
PMID: 21251800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12551874 | 1. Circulation. 2003 Jan 28;107(3):477-84. doi:
10.1161/01.cir.0000044917.74408.be.
FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor)
as a novel therapeutic strategy against heart failure.
Yano M(1), Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka
T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M.
Author information:
(1)Department of Medical Bioregulation, Division of Cardiovascular Medicine,
Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
[email protected]
Comment in
Circulation. 2003 Jan 28;107(3):378-80. doi:
10.1161/01.cir.0000046342.46135.cb.
BACKGROUND: The development of heart failure is tightly correlated with a
decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine
receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug,
the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process.
JTV519 is known to have a protective effect against Ca2+ overload-induced
myocardial injury.
METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right
ventricular pacing, with or without JTV519; SR were then isolated from dog left
ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart
failure were observed after 4 weeks of chronic right ventricular pacing, LV
systolic and diastolic functions were largely preserved, and LV remodeling was
prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak
from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there
was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts.
Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to
RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in
normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated,
whereas it was reversed in JTV519-treated hearts, returning the channel
phosphorylation toward the levels seen in normal hearts.
CONCLUSIONS: During the development of experimental heart failure, JTV519
prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced
the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less
severe heart failure.
DOI: 10.1161/01.cir.0000044917.74408.be
PMID: 12551874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20038616 | 1. Antimicrob Agents Chemother. 2010 Mar;54(3):1311-4. doi: 10.1128/AAC.00946-09.
Epub 2009 Dec 28.
Inhibition of Porphyromonas gingivalis biofilm by oxantel.
Dashper S(1), Ang CS, Liu SW, Paolini R, Veith P, Reynolds E.
Author information:
(1)Cooperative Research Centre for Oral Health Science, Melbourne Dental School,
Bio21 Institute, The University of Melbourne, Melbourne, Australia.
Porphyromonas gingivalis is a major pathogen of chronic periodontitis and exists
in a biofilm on the surface of the tooth root. Oxantel, a cholinergic
anthelmintic and fumarate reductase inhibitor, significantly inhibited biofilm
formation by P. gingivalis and disrupted established biofilms at concentrations
below its MIC against planktonic cells. Oxantel was more effective against P.
gingivalis in biofilm than metronidazole, a commonly used antibiotic for
periodontitis.
DOI: 10.1128/AAC.00946-09
PMCID: PMC2826025
PMID: 20038616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11757794 | 1. Curr Opin Investig Drugs. 2001 Jul;2(7):936-9.
JTV-519 Japan Tobacco.
Tse HF(1), Lam WF.
Author information:
(1)Queen Mary Hospital, University Department of Medicine, Pokfulam, Hong Kong.
[email protected]
Japan Tobacco is developing the mixed action ion channel blocker, JTV-519, which
has potential use as an antiarrhythmic [285800]. The drug is a novel
cardioprotectant derivative of 1,4-benzothiazepine for which phase I trials were
completed in the third quarter of 1998; phase II trials started in the fourth
quarter of 1998 for the potential treatment of myocardial infarction [320195].
Studies have shown that JTV-519 has a strong cardioprotective effect against
catecholamine-induced myocardial injury and against ischemia/reperfusion injury
[316749]. In experimental myofibrillar overcontraction models, it demonstrated
greater cardioprotectant effects than propranolol, verapamil and diltiazem
[171668].
PMID: 11757794 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7994803 | 1. Circulation. 1994 Dec;90(6):2635-44. doi: 10.1161/01.cir.90.6.2635.
Evidence of genetic heterogeneity in Romano-Ward long QT syndrome. Analysis of
23 families.
Towbin JA(1), Li H, Taggart RT, Lehmann MH, Schwartz PJ, Satler CA, Ayyagari R,
Robinson JL, Moss A, Hejtmancik JF.
Author information:
(1)Baylor College of Medicine, Department of Pediatrics, Houston, TX 77030.
BACKGROUND: The Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant
inherited trait characterized by prolonged QT interval on ECG, life-threatening
arrhythmias, syncope, and sudden death in affected individuals. A gene
responsible for this disorder has been shown to be linked to the Harvey ras-1
locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7
families. The purpose of this study was to determine, by analyzing 23 families
with LQTS for linkage to chromosome 11p, whether evidence exists for more than
one gene causing LQTS (ie, locus heterogeneity).
METHODS AND RESULTS: Twenty-three families (262 family members) were clinically
evaluated using medical histories, ECGs, and Holter recordings. Each corrected
QT interval (QTc) were determined using Bazett's formula. Blood for DNA
extraction and cell line immortalization was obtained after informed consent.
Southern blotting and polymerase chain reaction were performed, and linkage
analysis carried out using the LINKAGE computer program (v 5.03). Genetic
heterogeneity was determined using the HOMOG 2 (v 2.51) computer program.
Twenty-three families were studied for evidence of linkage to chromosome 11p
using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including
tyrosine hydroxylase (TH). Two-point linkage analysis using pTBB-2 and TH
markers was consistent with linkage in 15 of 23 families, with the maximum
single-family LOD score of +3.038 occurring at theta = 0. However, 8 of 23
families had negative LOD scores, with the values in 4 families being less than
-2 at theta = 0, consistent with exclusion of linkage. Analysis with the HOMOG
program was consistent with genetic heterogeneity (P < .0001). Multipoint
linkage data using pTBB-2 and TH were also examined for evidence of
heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding
the H-ras-1 locus also supported heterogeneity (P < .001).
CONCLUSIONS: In the 23 families with LQTS analyzed for linkage to the H-ras-1
locus on chromosome 11p15.5, 15 of 23 families had LOD scores consistent with
linkage. The remaining 8 of 23 families had negative LOD scores, 4 of which were
definitively excluded from linkage. Thus, genetic heterogeneity is definitively
(P < .001) demonstrated for this disorder.
DOI: 10.1161/01.cir.90.6.2635
PMID: 7994803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25668242 | 1. J Med Chem. 2015 Mar 12;58(5):2431-40. doi: 10.1021/jm501916k. Epub 2015 Feb
24.
C-Terminal modifications of apelin-13 significantly change ligand binding,
receptor signaling, and hypotensive action.
Murza A(1), Besserer-Offroy É, Côté J, Bérubé P, Longpré JM, Dumaine R, Lesur O,
Auger-Messier M, Leduc R, Sarret P, Marsault É.
Author information:
(1)Département de Pharmacologie et Physiologie, Faculté de Médecine et des
Sciences de la Santé, Université de Sherbrooke , Sherbrooke J1H 5N4, Québec
Canada.
Apelin is the endogenous ligand of the APJ receptor, a member of the G
protein-coupled receptor family. This system plays an important role in the
regulation of blood pressure and cardiovascular functions. To better understand
the role of its C-terminal Phe(13) residue on ligand binding, receptor
signaling, and hypotension, we report a series of modified analogues in which
Phe(13) was substituted by unnatural amino acids. These modifications delivered
new compounds exhibiting higher affinity and potency to inhibit cAMP
accumulation compared to apelin-13. In particular, analogues Bpa(13) or
(α-Me)Phe(13) were 30-fold more potent to inhibit cAMP accumulation than
apelin-13. Tyr(OBn)(13) substitution led to a 60-fold improvement in binding
affinity and induced stronger and more sustained drop in blood pressure compared
to apelin-13. Our study identified new potent analogues of apelin-13, which
represent valuable probes to better understand its structure-function
relationship.
DOI: 10.1021/jm501916k
PMID: 25668242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12796783 | 1. Nat Neurosci. 2003 Jul;6(7):717-23. doi: 10.1038/nn1071.
Postsynaptic requirement for Abl kinases in assembly of the neuromuscular
junction.
Finn AJ(1), Feng G, Pendergast AM.
Author information:
(1)Department of Pharmacology and Cancer Biology, Box 3813, Duke University
Medical Center, Durham, North Carolina 27710, USA.
Comment in
Nat Neurosci. 2003 Jul;6(7):653-4. doi: 10.1038/nn0703-653.
Agrin signals through the muscle-specific receptor tyrosine kinase (MuSK) to
cluster acetylcholine receptors (AChRs) on the postsynaptic membrane of the
neuromuscular junction (NMJ). This stands as the prevailing model of synapse
induction by a presynaptic factor, yet the agrin-dependent MuSK signaling
cascade is largely undefined. Abl1 (previously known as Abl) and the
Abl1-related gene product Abl2 (previously known as Arg) define a family of
tyrosine kinases that regulate actin structure and presynaptic axon guidance.
Here we show that the Abl kinases are critical mediators of postsynaptic
assembly downstream of agrin and MuSK. In mouse muscle, Abl kinases were
localized to the postsynaptic membrane of the developing NMJ. In cultured
myotubes, Abl kinase activity was required for agrin-induced AChR clustering and
enhancement of MuSK tyrosine phosphorylation. Moreover, MuSK and Abl kinases
effected reciprocal tyrosine phosphorylation and formed a complex after agrin
engagement. Our findings suggest that Abl kinases provide the developing synapse
with the kinase activity required for signal amplification and the intrinsic
cytoskeletal regulatory capacity required for assembly and remodeling.
DOI: 10.1038/nn1071
PMID: 12796783 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22136212 | 1. Int J Psychiatry Clin Pract. 2012 Sep;16(3):214-22. doi:
10.3109/13651501.2011.640939. Epub 2011 Dec 5.
Outpatient treatment of children and adolescents with antidepressants in
Croatia.
Maršanić VB(1), Margetić BA, Margetić B.
Author information:
(1)Psychiatric Hospital for Children and Youth, Zagreb, Croatia.
[email protected]
OBJECTIVE: This study is aimed to determine the prevalence and patterns of
antidepressants prescription in outpatient setting in Croatia.
METHODS: Retrospective analysis of outpatient visits to child psychiatrists by
persons aged 18 and younger that included prescription of antidepressants during
the year 2010. Antidepressant prescription data were identified by medication
class, drug entity and were analyzed in relation to age group, gender,
psychiatric diagnosis.
RESULTS: Antidepressants were prescribed to 139 youths (0.24‰), significantly
more to adolescents than pre-adolescents and for the treatment of depressive
disorders in females, and mixed disorders of emotions and conduct in males.
Sertraline was the most prescribed antidepressant for the treatment of major
depressive disorder, followed by fluvoxamine and tianeptine. Fluvoxamine was the
most prescribed antidepressant for the treatment of anxiety disorders and mixed
disorders of emotions and conduct. Off-label prescribing of antidepressants was
found in 85.6% of young patients.
CONCLUSIONS: This study found considerably lower prevalence and higher off-label
rate of antidepressant prescriptions to young people in Croatia to that in other
European Countries and in the United States. Selective serotonine reuptake
inhibitors comprise most of the antidepressant medications prescribed to young
people, reflecting trends in the developed countries.
DOI: 10.3109/13651501.2011.640939
PMID: 22136212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25491175 | 1. J Surg Res. 2015 Mar;194(1):18-24. doi: 10.1016/j.jss.2014.11.007. Epub 2014
Nov 13.
Enhancement of crystalloid cardioplegic protection by structural analogs of
apelin-12.
Pisarenko OI(1), Shulzhenko VS(2), Pelogeykina YA(2), Studneva IM(2).
Author information:
(1)Russian Cardiology Research and Production Complex, Moscow, Russia.
Electronic address: [email protected].
(2)Russian Cardiology Research and Production Complex, Moscow, Russia.
BACKGROUND: C-terminal fragments of adipokine apelin are able to attenuate
myocardial ischemia-reperfusion (I/R) injury, but whether their effects are
manifested during cardioplegic arrest remain obscure. This study was designed to
evaluate the efficacy of natural apelin-12
(H-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe-OH, A12) and its novel
structural analogs
(H-(N(α)Me)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH, AI, and
N(G)-Arg(N(G)NO2)-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-NH2, AII) as
additives to crystalloid cardioplegia and explore benefits of early reperfusion
with these peptides.
METHODS: Isolated working rat hearts subjected to normothermic global ischemia
and further reperfusion were used. St. Thomas' Hospital cardioplegic solution
No.2 (STH2) containing 140 μM A12, AI, or AII was infused for 5 min at 25 °C
before ischemia. In separate series, peptide administration was used for 5 min
after ischemia. Metabolic state of the hearts was evaluated by myocardial
content of high energy phosphates and lactate. Lactate dehydrogenase (LDH)
leakage was assessed in myocardial effluent on early reperfusion.
RESULTS: Addition of the peptides to STH2 enhanced functional and metabolic
recovery of reperfused hearts compared with those of control (STH2 without
additives). Cardioplegia with analog AII was the most effective and accompanied
by a reduction of postischemic LDH leakage. Infusion of A12, AI, or AII after
ischemia improved the majority indices of cardiac function and metabolic state
of the heart by the end of reperfusion. However, the overall protective effect
of the peptides was less than when they were added to STH2.
CONCLUSIONS: Enhancement of apelin bioavailability may minimize myocardial I/R
damage during cardiac surgery. Structural analogs of A12 are promising
components of clinical cardioplegic solutions.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jss.2014.11.007
PMID: 25491175 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25931124 | 1. J Biol Chem. 2015 Jun 5;290(23):14679-91. doi: 10.1074/jbc.M115.643817. Epub
2015 Apr 30.
Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes.
Than A(1), He HL(1), Chua SH(1), Xu D(2), Sun L(2), Leow MK(3), Chen P(4).
Author information:
(1)From the Bioengineering Program, School of Chemical and Biomedical
Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore
637457.
(2)the Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, and.
(3)the Endocrine and Diabetes Clinic, Tan Tock Seng Hospital, 11 Jalan Tan Tock
Seng, Singapore 308433, Singapore.
(4)From the Bioengineering Program, School of Chemical and Biomedical
Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore
637457, [email protected].
Brown adipose tissue expends energy in the form of heat via the mitochondrial
uncoupling protein UCP1. Recent studies showed that brown adipose tissue is
present in adult humans and may be exploited for its anti-obesity and
anti-diabetes actions. Apelin is an adipocyte-derived hormone that plays
important roles in energy metabolism. Here, we report that apelin-APJ signaling
promotes brown adipocyte differentiation by increasing the expressions of brown
adipogenic and thermogenic transcriptional factors via the PI3K/Akt and AMPK
signaling pathways. It is also found that apelin relieves the TNFα inhibition on
brown adipogenesis. In addition, apelin increases the basal activity of brown
adipocytes, as evidenced by the increased PGC1α and UCP1 expressions,
mitochondrial biogenesis, and oxygen consumption. Finally, we provide both in
vitro and in vivo evidence that apelin is able to increase the brown-like
characteristics in white adipocytes. This study, for the first time, reveals the
brown adipogenic and browning effects of apelin and suggests a potential
therapeutic route to combat obesity and related metabolic disorders.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M115.643817
PMCID: PMC4505534
PMID: 25931124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15176430 | 1. Ann Med. 2004;36 Suppl 1:92-7. doi: 10.1080/17431380410032490.
Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and
genetic heterogeneity.
Donaldson MR(1), Yoon G, Fu YH, Ptacek LJ.
Author information:
(1)Department of Human Molecular Biology and Genetics, University of Utah, Salt
Lake City, USA.
Due to its varied and variable phenotypes, Andersen-Tawil syndrome (ATS) holds a
unique place in the field of channelopathies. Patients with ATS typically
present with the triad of periodic paralysis, cardiac arrhythmias, and
developmental dysmorphisms. Although penetrance of ATS is high, disease
expression and severity are remarkably variable. Mutations in KCNJ2 are the
primary cause of ATS with 21 mutations discovered in 30 families. These
mutations affect channel function through heterogeneous mechanisms, including
reduced PIP2-related channel activation and altered pore function. Aside from
KCNJ2-based ATS, the genetic basis of this disease in nearly 40% of cases is
unknown. Other ATS genes likely share a common pathway or function with Kir2.1
or facilitate the activity of this ion channel. In this review, we explore
hypotheses explaining the pathogenesis, expression, and variability of ATS.
DOI: 10.1080/17431380410032490
PMID: 15176430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2771275 | 1. N Z Med J. 1989 Jul 12;102(871):340-1.
Congenital long QT syndrome in adults.
Crozier IG(1), Loughnan A, Dow LJ, Low CJ, Ikram H.
Author information:
(1)Department of Cardiology, Princess Margaret Hospital, Christchurch.
Comment in
N Z Med J. 1989 Nov 22;102(880):620-1.
A family with the Romano-Ward syndrome is presented. This family showed typical
features of this syndrome with QT prolongation, torsades de pointes ventricular
tachycardia, sudden death and an autosomal dominant inheritance pattern. The
index case presented with an exacerbation of torsades de pointes ventricular
tachycardia from diuretic induced hypokalaemia, and responded to diuretic
withdrawal and beta blocker therapy.
PMID: 2771275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11502581 | 1. Am J Physiol Cell Physiol. 2001 Sep;281(3):C1029-37. doi:
10.1152/ajpcell.2001.281.3.C1029.
Role of phospholamban in the modulation of arterial Ca(2+) sparks and
Ca(2+)-activated K(+) channels by cAMP.
Wellman GC(1), Santana LF, Bonev AD, Nelson MT.
Author information:
(1)Department of Pharmacology, University of Vermont, Burlington, Vermont 05405,
USA.
Phospholamban (PLB) inhibits the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and
this inhibition is relieved by cAMP-dependent protein kinase (PKA)-mediated
phosphorylation. The role of PLB in regulating Ca(2+) release through
ryanodine-sensitive Ca(2+) release channels, measured as Ca(2+) sparks, was
examined using smooth muscle cells of cerebral arteries from PLB-deficient
("knockout") mice (PLB-KO). Ca(2+) sparks were monitored optically using the
fluorescent Ca(2+) indicator fluo 3 or electrically by measuring transient
large-conductance Ca(2+)-activated K(+) (BK) channel currents activated by
Ca(2+) sparks. Basal Ca(2+) spark and transient BK current frequency were
elevated in cerebral artery myocytes of PLB-KO mice. Forskolin, an activator of
adenylyl cyclase, increased the frequency of Ca(2+) sparks and transient BK
currents in cerebral arteries from control mice. However, forskolin had little
effect on the frequency of Ca(2+) sparks and transient BK currents from PLB-KO
cerebral arteries. Forskolin or PLB-KO increased SR Ca(2+) load, as measured by
caffeine-induced Ca(2+) transients. This study provides the first evidence that
PLB is critical for frequency modulation of Ca(2+) sparks and associated BK
currents by PKA in smooth muscle.
DOI: 10.1152/ajpcell.2001.281.3.C1029
PMID: 11502581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3730367 | 1. Biochemistry. 1986 Jun 3;25(11):3415-24. doi: 10.1021/bi00359a048.
Characterization and partial purification of cardiac sarcoplasmic reticulum
phospholamban kinase.
Molla A, Demaille JG.
Phospholamban, the cardiac sarcoplasmic reticulum proteolipid, is phosphorylated
by cAMP-dependent protein kinase, by Ca2+/phospholipid-dependent protein kinase,
and by an endogenous Ca2+/calmodulin-dependent protein kinase, the identity of
which remains to be defined. The aim of this study was therefore to characterize
the latter kinase, called phospholamban kinase. Phospholamban kinase was
purified approximately 42-fold with a yield of 11%. The purified fraction
exhibits a specific activity of 6.5 nmol of phosphate incorporated into
exogenous phospholamban per minute per milligram of protein. Phospholamban
kinase appears to be a high molecular weight enzyme and presents a broad
substrate specificity, synapsin-1, glycogen synthase, and smooth muscle myosin
regulatory light chain being the best substrates. Phospholamban kinase
phosphorylates synapsin-1 on a Mr 30 000 peptide. The enzyme exhibits an optimum
pH of 8.6, a Km for ATP of 9 microM, and a requirement for Mg2+ ions. These data
suggest that phospholamban kinase might be an isoenzyme of the multifunctional
Ca2+/calmodulin-dependent protein kinase. Consequently we have searched for Mr
50 000-60 000 phosphorylatable subunits among cardiac sarcoplasmic reticulum
proteins. A Mr 56 000 protein was found to be phosphorylated in the presence of
Ca2+/calmodulin. Such phosphorylation alters the electrophoretic migration
velocity of the protein. In addition, this protein that binds calmodulin was
always found to be present in fractions containing phospholamban kinase
activity. This Mr 56 000 protein is therefore a good candidate for being a
subunit of phospholamban kinase. However, the Mr 56 000 calmodulin-binding
protein and the Mr 53 000 intrinsic glycoprotein which binds ATP are two
distinct entities.
DOI: 10.1021/bi00359a048
PMID: 3730367 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9500553 | 1. Nat Genet. 1998 Mar;18(3):280-2. doi: 10.1038/ng0398-280.
An intramolecular SH3-domain interaction regulates c-Abl activity.
Barilá D(1), Superti-Furga G.
Author information:
(1)European Molecular Biology Laboratory, Heidelberg, Germany.
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine
kinase (c-Abl) that has been implicated in processes of cell differentiation,
cell division, cell adhesion and stress response. Alterations of ABL1 by
chromosomal rearrangement or viral transduction can lead to malignant
transformation. Activity of the c-Abl protein is negatively regulated by its SH3
domain through an unknown mechanism, and deletion of the SH3 domain turns ABL1
into an oncogene. We present evidence for an intramolecular inhibitory
interaction of the SH3 domain with the catalytic domain and with the linker
between the SH2 and catalytic domain (SH2-CD linker). Site-directed mutations in
each of these three elements activate c-Abl. Mutations in the linker cause a
conformational change of the molecule and increase binding of the SH3 domain to
peptide ligands. Individual mutation of two charged residues in the SH3 and
catalytic domain activates c-Abl, while inhibition is restored in the double
reciprocal mutant. We propose that regulators of c-Abl will have opposite
effects on its activity depending on their ability to favour or disrupt these
intramolecular interactions.
DOI: 10.1038/ng0398-280
PMID: 9500553 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15909986 | 1. Biochemistry. 2005 May 31;44(21):7713-24. doi: 10.1021/bi048011i.
Intermolecular conformational coupling and free energy exchange enhance the
catalytic efficiency of cardiac muscle SERCA2a following the relief of
phospholamban inhibition.
Mahaney JE(1), Albers RW, Waggoner JR, Kutchai HC, Froehlich JP.
Author information:
(1)Biomedical Science Division, Edward Via Virginia College of Osteopathic
Medicine, Blacksburg, Virginia 24060, USA.
Activation of cardiac muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) by
beta1-agonists involves cAMP- and PKA-dependent phosphorylation of phospholamban
(PLB), which relieves the inhibitory effects of PLB on SERCA2a. To investigate
the mechanism of SERCA2a activation, we compared the kinetic properties of
SERCA2a expressed with (+) and without (-) PLB in High Five insect cell
microsomes to those of SERCA1 and SERCA2a in native skeletal and cardiac muscle
SR. Both native SERCA1 and expressed SERCA2a without PLB exhibited high-affinity
(10-50 microM) activation of pre-steady-state catalytic site dephosphorylation
by ATP, steady-state accumulation of the ADP-sensitive phosphoenzyme (E1P), and
a rapid phase of EGTA-induced phosphoenzyme (E2P) hydrolysis. In contrast,
SERCA2a in native cardiac SR vesicles and expressed SERCA2a with PLB lacked the
high-affinity activation by ATP and the rapid phase of E2P hydrolysis, and
exhibited low steady-state levels of E1P. The results indicate that the kinetic
differences in Ca2+ transport between skeletal and cardiac SR are due to the
presence of phospholamban in cardiac SR, and not due to isoform-dependent
differences between SERCA1 and SERCA2a. Therefore, the results are discussed in
terms of a model in which PLB interferes with SERCA2a oligomeric interactions,
which are important for the mechanism of Ca2+ transport in skeletal muscle
SERCA1 [Mahaney, J. E., Thomas, D. D., and Froehlich, J. P. (2004) Biochemistry
43, 4400-4416]. We propose that intermolecular coupling of SERCA2a molecules
during catalytic cycling is obligatory for the changes in Ca2+ transport
activity that accompany the relief of PLB inhibition of the cardiac SR
Ca2+-ATPase.
DOI: 10.1021/bi048011i
PMID: 15909986 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10330247 | 1. Am J Physiol. 1999 May;276(5):H1625-33. doi:
10.1152/ajpheart.1999.276.5.H1625.
Ser16 prevails over Thr17 phospholamban phosphorylation in the beta-adrenergic
regulation of cardiac relaxation.
Kuschel M(1), Karczewski P, Hempel P, Schlegel WP, Krause EG, Bartel S.
Author information:
(1)Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
Phospholamban is a critical regulator of sarcoplasmic reticulum Ca2+-ATPase and
myocardial contractility. To determine the extent of cross signaling between
Ca2+ and cAMP pathways, we have investigated the beta-adrenergic-induced
phosphorylation of Ser16 and Thr17 of phospholamban in perfused rat hearts using
antibodies recognizing phospholamban phosphorylated at either position.
Isoproterenol caused the dose-dependent phosphorylation of Ser16 and Thr17 with
strikingly different half-maximal values (EC50 = 4.5 +/- 1.6 and 28. 2 +/- 1.4
nmol/l, respectively). The phosphorylation of Ser16 induced by isoproterenol,
forskolin, or 3-isobutyl-1-methylxanthine correlated to increased cardiac
relaxation (r = 0.96), whereas phosphorylation of Thr17 did not. Elevation of
extracellular Ca2+ did not induce phosphorylation at Thr17; only in the presence
of a submaximal dose of isoproterenol, phosphorylation at Thr17 increased
eightfold without additional effects on relaxation rate. Thr17 phosphorylation
was partially affected by ryanodine and was completely abolished in the presence
of 1 micromol/l verapamil or nifedipine. The data indicate that 1)
phosphorylation of phospholamban at Ser16 by cAMP-dependent protein kinase is
the main regulator of beta-adrenergic-induced cardiac relaxation definitely
preceding Thr17 phosphorylation and 2) the beta-adrenergic-mediated
phosphorylation of Thr17 by Ca2+-calmodulin-dependent protein kinase required
influx of Ca2+ through the L-type Ca2+ channel.
DOI: 10.1152/ajpheart.1999.276.5.H1625
PMID: 10330247 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21435002 | 1. Eur J Haematol. 2011 May;86(5):361-71. doi: 10.1111/j.1600-0609.2011.01586.x.
Epub 2011 Mar 23.
ABL1 fusion genes in hematological malignancies: a review.
De Braekeleer E(1), Douet-Guilbert N, Rowe D, Bown N, Morel F, Berthou C, Férec
C, De Braekeleer M.
Author information:
(1)Université de Brest, Faculté de Médecine et des Sciences de la Santé, Brest
Institut National de la Santé et de la Recherche Médicale (INSERM), Brest CHRU
Brest, Hôpital Morvan, Service de Cytogénétique, Cytologie et Biologie de la
Reproduction, Brest, France.
Chromosomal rearrangements involving the ABL1 gene, leading to a BCR-ABL1 fusion
gene, have been mainly associated with chronic myeloid leukemia and B-cell acute
lymphoblastic leukemia (ALL). At present, six other genes have been shown to
fuse to ABL1. The kinase domain of ABL1 is retained in all chimeric proteins
that are also composed of the N-terminal part of the partner protein that often
includes a coiled-coil or a helix-loop-helix domain. These latter domains allow
oligomerization of the protein that is required for tyrosine kinase activation,
cytoskeletal localization, and neoplastic transformation. Fusion genes that have
a break in intron 1 or 2 (BCR-ABL1, ETV6-ABL1, ZMIZ1-ABL1, EML1-ABL1, and
NUP214-ABL1) have transforming activity, although NUP214-ABL1 requires
amplification to be efficient. The NUP214-ABL1 gene is the second most prevalent
fusion gene involving ABL1 in malignant hemopathies, with a frequency of 5% in
T-cell ALL. Both fusion genes (SFPQ-ABL1 and RCSD1-ABL1) characterized by a
break in intron 4 of ABL1 are associated with B-cell ALL, as the chimeric
proteins lacked the SH2 domain of ABL1. Screening for ABL1 chimeric genes could
be performed in patients with ALL, more particularly in those with T-cell ALL
because ABL1 modulates T-cell development and plays a role in cytoskeletal
remodeling processes in T cells.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0609.2011.01586.x
PMID: 21435002 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3957897 | 1. J Biochem. 1986 Jan;99(1):41-53. doi: 10.1093/oxfordjournals.jbchem.a135478.
Subunit structure and multiple phosphorylation sites of phospholamban.
Imagawa T, Watanabe T, Nakamura T.
The phosphorylation-induced mobility shift of the high molecular weight form of
phospholamban (24,500 daltons) in the cardiac sarcoplasmic reticulum produced on
3',5'-cyclic AMP (cAMP)-dependent phosphorylation with 5 mM ATP was resolved
into five clear steps on sodium dodecyl sulfate polyacrylamide gel
electrophoresis (SDS-PAGE), and on Ca2+-calmodulin-dependent phosphorylation
into ten steps. The mobility shift of the low molecular weight form of
phospholamban (less than 14,400 daltons) in these reactions occurred in one step
and two steps, respectively. With the two protein kinase activities, the
electrophoretic pattern of the mobility shifts of the high and low molecular
weight forms of phospholamban was similar to that obtained with
Ca2+-calmodulin-dependent protein kinase alone. The results of pulse-chase
experiments involving the centrifuge column method suggested that the site(s) of
phosphorylation by cAMP- and Ca2+-calmodulin-dependent protein kinase activities
are on the same phospholamban molecule. Two-dimensional tryptic peptide maps of
phosphorylated phospholamban indicated that cAMP-dependent protein kinase
phosphorylates at a single site, A, and Ca2+-calmodulin-dependent protein kinase
phosphorylates at sites C1 and C2 in the low molecular weight form, where A is
different from C1 but may be the same as C2. The high molecular weight form of
phospholamban is suggested to be a pentamer of identical monomers (low molecular
weight form) having one phosphorylation site for cAMP-dependent protein kinase
and two for Ca2+-calmodulin-dependent protein kinase.
DOI: 10.1093/oxfordjournals.jbchem.a135478
PMID: 3957897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22345622 | 1. Bioinformatics. 2012 Apr 15;28(8):1062-9. doi: 10.1093/bioinformatics/bts085.
Epub 2012 Feb 17.
Signal analysis for genome-wide maps of histone modifications measured by
ChIP-seq.
Beck D(1), Brandl MB, Boelen L, Unnikrishnan A, Pimanda JE, Wong JW.
Author information:
(1)Lowy Cancer Research Centre, Prince of Wales Clinical School, University of
New South Wales, Sydney, NSW 2052, Australia. [email protected]
MOTIVATION: Chromatin structure, including post-translational modifications of
histones, regulates gene expression, alternative splicing and cell identity.
ChIP-seq is an increasingly used assay to study chromatin function. However,
tools for downstream bioinformatics analysis are limited and are only based on
the evaluation of signal intensities. We reasoned that new methods taking into
account other signal characteristics such as peak shape, location and
frequencies might reveal new insights into chromatin function, particularly in
situation where differences in read intensities are subtle.
RESULTS: We introduced an analysis pipeline, based on linear predictive coding
(LPC), which allows the capture and comparison of ChIP-seq histone profiles.
First, we show that the modeled signal profiles distinguish differentially
expressed genes with comparable accuracy to signal intensities. The method was
robust against parameter variations and performed well up to a signal-to-noise
ratio of 0.55. Additionally, we show that LPC profiles of activating and
repressive histone marks cluster into distinct groups and can be used to predict
their function.
AVAILABILITY AND IMPLEMENTATION:
http://www.cancerresearch.unsw.edu.au/crcweb.nsf/page/LPCHP A Matlab
implementation along with usage instructions and an example input file are
available from: http://www.cancerresearch.unsw.edu.au/crcweb.nsf/page/LPCHP.
DOI: 10.1093/bioinformatics/bts085
PMID: 22345622 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16600289 | 1. J Mol Cell Cardiol. 2006 May;40(5):619-28. doi: 10.1016/j.yjmcc.2006.02.002.
Down regulation of the L-type Ca2+ channel, GRK2, and phosphorylated
phospholamban: protective mechanisms for the denervated failing heart.
Yatani A(1), Shen YT, Yan L, Chen W, Kim SJ, Sano K, Irie K, Vatner SF, Vatner
DE.
Author information:
(1)Cardiovascular Research Institute and Department of Cell Biology and
Molecular Medicine, University of Medicine and Dentistry of New Jersey
(UMDNJ)-New Jersey Medical School, Newark, 07103, USA. [email protected]
We previously found that a canine model of selective surgical ventricular
denervation (VD), which does not permit increased sympathetic tone during the
pathogenesis of heart failure (HF), tolerated the development of HF better than
controls. To investigate the cellular mechanisms, we examined cellular
contraction and L-type Ca(2+) channel currents (I(Ca)) and their responses to
beta-adrenergic receptor (beta-AR) stimulation in left ventricular myocytes from
1) control, 2) VD, 3) HF induced by rapid pacing, and 4) HF induced in VD
(VD-HF) dogs. The magnitude of myocyte contraction and rate of relaxation in VD
were similar to control but were depressed in both HF and VD-HF. These changes
were associated with reduced protein expression of sarcoplasmic reticulum
Ca(2+)-ATPase (SERCA2a) and protein kinase A phosphorylated phospholamban (PLB),
which was reduced in HF, but essentially abolished in VD-HF. beta-AR kinase
(GRK2) was increased in HF but reduced in VD-HF. Basal I(Ca) density did not
differ among control, VD, and HF groups, but VD-HF myocytes showed a markedly
reduced I(Ca) density (approximately 40%). Compared to controls, the sensitivity
of I(Ca) to isoproterenol (ISO), was significantly higher in VD, but reduced in
HF. While I(Ca) responses to ISO in VD-HF were maintained at control levels, the
amplitude of the ISO-stimulated I(Ca) was significantly smaller (approximately
50%) compared with HF myocytes. The relative decrease in Ca(2+) influx due to
downregulation of I(Ca) density may contribute to the cardioprotective effects
in VD-HF hearts by preventing Ca(2+) overload during the development of HF.
These findings, in combination with the virtual abolition of phosphorylated PLB
in VD-HF and the decrease in GRK2, may explain, in part, why VD dogs tolerate
the development of HF better than control dogs.
DOI: 10.1016/j.yjmcc.2006.02.002
PMID: 16600289 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14577598 | 1. Mol Cell Biochem. 2003 Oct;252(1-2):239-46. doi: 10.1023/a:1025504709518.
Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing
during ischemia and response to a beta-adrenergic challenge.
Mundiña-Weilenmann C(1), Said M, Vittone L, Ferrero P, Mattiazzi A.
Author information:
(1)Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas,
Universidad Nacional de La Plata, La Plata, Argentina.
The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused
hearts remains controversial. Although a decrease in the phosphorylation of both
PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported,
experiments from our laboratory failed to detect this decrease. In an attempt to
elucidate the cause for this discrepancy, experiments were performed in
Langendorff-perfused rat hearts with two main goals: (1) To determine whether
keeping pacing during ischemia, a protocol followed in other
ischemia-reperfusion models, decreases the phosphorylation of PLB residues,
below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic
challenge allows to detect a decrease in the ability of PLB to be phosphorylated
in ischemia-reperfused hearts. Hearts were submitted to a global
ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during
ischemia, and phosphorylation of PLB residues was assessed by immunodetection.
The recovery of contractility upon reperfusion was lower in P vs. NP hearts.
Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This
increase appeared earlier in P hearts and was significantly diminished by
catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the
beginning of ischemia and the onset of reperfusion. The ischemia-induced
phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and
inhibited by the calcium channel blocker, nifedipine, whereas the
reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP
hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor
KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at
any time during ischemia and reperfusion. However, the phosphorylation,
inotropic and lusitropic response to beta-adrenergic stimulation was
significantly decreased both in P and NP hearts.
DOI: 10.1023/a:1025504709518
PMID: 14577598 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17548345 | 1. J Biol Chem. 2007 Jul 20;282(29):20968-76. doi: 10.1074/jbc.M703516200. Epub
2007 Jun 4.
Mechanism of reversal of phospholamban inhibition of the cardiac Ca2+-ATPase by
protein kinase A and by anti-phospholamban monoclonal antibody 2D12.
Chen Z(1), Akin BL, Jones LR.
Author information:
(1)Krannert Institute of Cardiology and the Department of Medicine, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA.
Our model of phospholamban (PLB) regulation of the cardiac Ca(2+)-ATPase in
sarcoplasmic reticulum (SERCA2a) states that PLB binds to the Ca(2+)-free, E2
conformation of SERCA2a and blocks it from transitioning from E2 to E1, the
Ca(2+)-bound state. PLB and Ca(2+) binding to SERCA2a are mutually exclusive,
and PLB inhibition of SERCA2a is manifested as a decreased apparent affinity of
SERCA2a for Ca(2+). Here we extend this model to explain the reversal of SERCA2a
inhibition that occurs after phosphorylation of PLB at Ser(16) by protein kinase
A (PKA) and after binding of the anti-PLB monoclonal antibody 2D12, which
recognizes residues 7-13 of PLB. Site-specific cysteine variants of PLB were
co-expressed with SERCA2a, and the effects of PKA phosphorylation and 2D12 on
Ca(2+)-ATPase activity and cross-linking to SERCA2a were monitored. In
Ca(2+)-ATPase assays, PKA phosphorylation and 2D12 partially and completely
reversed SERCA2a inhibition by decreasing K(Ca) values for enzyme activation,
respectively. In cross-linking assays, cross-linking of PKA-phosphorylated PLB
to SERCA2a was inhibited at only two of eight sites when conducted in the
absence of Ca(2+) favoring E2. However, at a subsaturating Ca(2+) concentration
supporting some E1, cross-linking of phosphorylated PLB to SERCA2a was
attenuated at all eight sites. K(Ca) values for cross-linking inhibition were
decreased nearly 2-fold at all sites by PLB phosphorylation, demonstrating that
phosphorylated PLB binds more weakly to SERCA2a than dephosphorylated PLB. In
parallel assays, 2D12 blocked PLB cross-linking to SERCA2a at all eight sites
regardless of Ca(2+) concentration. Our results demonstrate that 2D12 restores
maximal Ca(2+)-ATPase activity by physically disrupting the binding interaction
between PLB and SERCA2a. Phosphorylation of PLB by PKA weakens the binding
interaction between PLB and SERCA2a (yielding more PLB-free SERCA2a molecules at
intermediate Ca(2+) concentrations), only partially restoring Ca(2+) affinity
and Ca(2+)-ATPase activity.
DOI: 10.1074/jbc.M703516200
PMID: 17548345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8098062 | 1. J Reprod Med. 1993 Mar;38(3):233-4.
Syncope and sudden arrhythmic death complicating pregnancy. A case report of
Romano-Ward syndrome.
McCurdy CM Jr(1), Rutherford SE, Coddington CC.
Author information:
(1)Department of Obstetrics and Gynecology, Naval Hospital Portsmouth, Virginia.
Romano-Ward syndrome is a subtype of prolonged QT syndrome with autosomal
dominant inheritance. Stress-induced syncope and sudden death are secondary to
ventricular tachydysrhythmias. A case report of Romano-Ward syndrome
complicating pregnancy is presented. Successful therapy with propranolol for
life-threatening dysrhythmias was achieved. An excellent neonatal outcome
occurred.
PMID: 8098062 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22971156 | 1. Expert Opin Ther Pat. 2012 Oct;22(10):1233-49. doi:
10.1517/13543776.2012.723693. Epub 2012 Sep 13.
Selective JAK1 inhibitor and selective Tyk2 inhibitor patents.
Norman P(1).
Author information:
(1)Norman Consulting, 18 Pink Lane, Burnham, Bucks, SL1 8JW, UK.
[email protected]
INTRODUCTION: The JAK family comprises of the four non-receptor tyrosine kinases
JAK1, JAK2, JAK3 and Tyk2, which play key, but differing, roles in cytokine
receptor signal transduction. A non-selective JAK inhibitor, ruxolitinib, has
recently been approved to treat myelofibrosis whereas tofacitinib is poised for
approval to treat rheumatoid arthritis. Selective inhibition of JAK3, JAK1 or
Tyk2 provides the opportunity to achieve clinical efficacy in the treatment of
inflammatory diseases while reducing the risk of dose-limiting effects
attributable to JAK2 inhibition.
AREAS COVERED: This review considers the small number of published patent
filings that claim either selective JAK1 or selective Tyk2 inhibitors. These are
considered in the context of the considerably larger number of disclosures and
patent filings claiming selective JAK2 or JAK3 inhibitors.
EXPERT OPINION: The recent disclosure of the clinical efficacy of a selective
JAK1 inhibitor (GLPG-0634) in rheumatoid arthritis and detailed disclosure of
the some potent and highly selective JAK1 inhibitors provide a clear stimulus
for further activity in this area. The availability of a selective Tyk2
inhibitor will provide the opportunity for better understanding of the
physiological role of this kinase. Recent patent applications indicate that Tyk2
selectivity is achievable and Tyk2 inhibitors have potential in the treatment of
multiple sclerosis.
DOI: 10.1517/13543776.2012.723693
PMID: 22971156 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21884580 | 1. BMC Immunol. 2011 Aug 31;12:51. doi: 10.1186/1471-2172-12-51.
Inhibitory effects of the JAK inhibitor CP690,550 on human CD4(+) T lymphocyte
cytokine production.
Migita K(1), Miyashita T, Izumi Y, Koga T, Komori A, Maeda Y, Jiuchi Y, Aiba Y,
Yamasaki S, Kawakami A, Nakamura M, Ishibashi H.
Author information:
(1)Department of Rheumatology and Clinical Research Center, NHO Nagasaki Medical
Center, Kubara 2-1001-1, Omura 856-8652, Japan. [email protected]
BACKGROUND: The new JAK3 inhibitor, CP690,550, has shown efficacy in the
treatment of rheumatoid arthritis. The present study was undertaken to assess
the effects of CP690,550 on cytokine production and cellular signaling in human
CD4(+) T cells.
RESULTS: CD4(+) T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-γ in following
stimulation with a CD3 antibody. At the optimal concentration, CP690,550 almost
completely inhibited the production of IL-4, IL-17, IL-22 and IFN-γ from these
activated CD4(+) T cells, but only had marginal effects on IL-2 production.
Moreover CP690,550 inhibited anti-CD3-induced phosphorylation of STAT1, STAT3,
STAT4, STAT5, and STAT6, but not the TCR-associated phosphorylation of ZAP-70.
CONCLUSIONS: Therefore, CP690,550-mediated modification of the JAK/STAT pathway
may be a new immunosuppressive strategy in the treatment of autoimmune diseases.
DOI: 10.1186/1471-2172-12-51
PMCID: PMC3179939
PMID: 21884580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23659470 | 1. Pain Med. 2013 Jul;14(7):1010-20. doi: 10.1111/pme.12131. Epub 2013 May 9.
Improving access to care for women veterans suffering from chronic pain and
depression associated with trauma.
Tan G(1), Teo I, Srivastava D, Smith D, Smith SL, Williams W, Jensen MP.
Author information:
(1)National University of Singapore, Singapore, Singapore. [email protected]
OBJECTIVE: Access to care has become a priority for the Veterans Administration
(VA) health care system as a significant number of veterans enrolled in the VA
health care system reside in rural areas. The feasibility and effects of a novel
clinical intervention that combined group therapy and biofeedback training was
evaluated on women veterans living in rural areas.
METHODS: The study was conducted at selected community-based outpatient clinics
(CBOCs) in Texas. Thirty four women veterans with chronic pain and comorbid
depression and/or posttraumatic stress disorder (PTSD) were recruited. Five
sessions of education/therapy were delivered via telemedicine in combination
with daily home practice of a portable biofeedback device (Stress Eraser®,
Helicor, New York, NY, USA). Participants responded to self-report
questionnaires at baseline, at posttreatment, and at 6-week follow-up. Daily
practice logs were also maintained by participants.
RESULTS: The clinical protocol was acceptable, easy to administer, and
associated with statistically significant decreases in self-reported pain
unpleasantness, pain interference, depressive symptoms, PTSD symptoms, and sleep
disturbance at posttreatment. Improvements were maintained at 6-week follow-up.
Qualitative analyses indicated that many participants 1) wished to continue to
meet as a support group in their respective CBOCs and 2) felt less isolated and
more empowered to cope with their problems of daily living as a result of the
treatment.
CONCLUSIONS: It is feasible to provide treatment to women veterans living in
rural areas by utilizing video-teleconferencing technology between larger VA
medical centers and facilities at CBOCs in more rural settings. A controlled
trial of the intervention is warranted.
Published 2013. This article is a U.S. Government work and is in the public
domain in the USA.
DOI: 10.1111/pme.12131
PMID: 23659470 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22893792 | 1. Genes Cancer. 2012 Jan;3(1):71-81. doi: 10.1177/1947601912452665.
Novel Insights into the Molecular Mechanism of Action of DNA Hypomethylating
Agents: Role of Protein Kinase C δ in Decitabine-Induced Degradation of DNA
Methyltransferase 1.
Datta J(1), Ghoshal K, Motiwala T, Jacob ST.
Author information:
(1)Department of Molecular and Cellular Biochemistry, The Ohio State University,
Columbus, OH, USA.
We have previously demonstrated proteasomal degradation of DNMT1 in mammalian
cells following treatment with several DNA hypomethylating agents. Here, we
demonstrate dose-dependent degradation of Dnmt1 in mouse embryonic stem (ES)
cells expressing catalytic site mutant (cys-ser), confirming that the covalent
bond formation between Dnmt1 and decitabine-incorporated DNA is not essential
for this process. DNMT1o, the oocyte-specific isoform that lacks the N-terminal
118-amino acid domain, did not undergo decitabine-mediated degradation, which
further proves the requirement of multiple domains including nuclear
localization signal, KEN box, and BAH domains for this process. Analysis of
glycerol density gradient fractions of micrococcal nuclease-digested nuclei
showed that both nucleosomal and nucleoplasmic DNMT1 are degraded upon
decitabine treatment. Among different inhibitors tested, the inhibitors of the
proteasomal pathway and several protein kinases impeded decitabine-induced DNMT1
degradation. The maximal effect caused by inhibiting protein kinase C (PKC)
persuaded us to investigate further its role in decitabine-mediated DNMT1
degradation. Blockage of the degradation process after treatment with rottlerin,
an inhibitor of PKCδ, or after siRNA-mediated depletion of PKCδ, indicated that
this protein kinase is involved in decitabine-mediated depletion of DNMT1. PKCδ
interacted with and phosphorylated DNMT1 in vitro. Moreover, rottlerin inhibited
both basal and decitabine-induced phosphorylation of DNMT1. These studies
provide substantial evidence that decitabine-induced degradation of the
maintenance methyltransferase DNMT1 does not require covalent bond formation
with the substrate and also elucidate its underlying molecular mechanism.
DOI: 10.1177/1947601912452665
PMCID: PMC3415671
PMID: 22893792
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/11812163 | 1. J Mol Cell Cardiol. 2002 Jan;34(1):39-50. doi: 10.1006/jmcc.2001.1488.
Time course and mechanisms of phosphorylation of phospholamban residues in
ischemia-reperfused rat hearts. Dissociation of phospholamban phosphorylation
pathways.
Vittone L(1), Mundiña-Weilenmann C, Said M, Ferrero P, Mattiazzi A.
Author information:
(1)Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas,
Universidad Nacional de La Plata, 60 y 120, La Plata, Argentina.
Sarcoplasmic reticulum (SR) dysfunction is one of the multiple alterations that
occurs in ischemia-reperfused hearts. Because SR function is regulated by
phosphorylation of phospholamban (PLB), a SR protein phosphorylated by
cAMP-dependent protein kinase (PKA) at Ser(16)and Ca(2+)-calmodulin-dependent
protein kinase (CaMKII) at Thr(17), the phosphorylation of these residues during
ischemia and reperfusion was examined in Langendorff-perfused rat hearts.
Ser(16)phosphorylation increased significantly after 20 min of ischemia from
2.5+/-0.6% to 99.8+/-25.5% of maximal isoproterenol-induced site-specific
phosphorylation and decreased to control values immediately after reperfusion.
Thr(17)phosphorylation transiently increased at 2-5 min of ischemia and at 1 min
of reperfusion (R1, 166.2+/-28.2%). The ischemia-induced increase in
Ser(16)phosphorylation was significantly diminished in hearts from
catecholamine-depleted animals and/or after beta-blockade and abolished in the
presence of the PKA-inhibitor, H-89. Thr(17)phosphorylation at the beginning of
ischemia was blunted by nifedipine, whereas at R1 it was significantly
diminished by perfusion with 0 m m Ca(2+)in the presence of EGTA and by the
Na(+)/Ca(2+)exchanger inhibitor KB-R7943. KN-93, used to specifically inhibit
CaMKII, decreased Thr(17)phosphorylation at R1 and significantly prolonged half
relaxation time. The results demonstrated a dissociation between the
phosphorylation of PLB sites, being phosphorylation of Ser(16)dependent on the
beta-adrenergic cascade during ischemia and phosphorylation of Thr(17)on
Ca(2+)influx both, at the beginning of ischemia and reperfusion. Phosphorylation
of Thr(17)at the onset of reflow may provide the cell a mechanism to cope with
Ca(2+)overload, transiently favoring the recovery of relaxation during early
reperfusion.
Copyright 2002 Academic Press.
DOI: 10.1006/jmcc.2001.1488
PMID: 11812163 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24012954 | 1. Cell Signal. 2013 Dec;25(12):2604-12. doi: 10.1016/j.cellsig.2013.08.023. Epub
2013 Sep 3.
Proteomic-based identification of Apg-2 as a therapeutic target for chronic
myeloid leukemia.
Li Y(1), Chen X, Shi M, Wang H, Cao W, Wang X, Li C, Feng W.
Author information:
(1)Department of Clinical Hematology, Key Laboratory of the Laboratory of
Medical Diagnostics of the Ministry of Education, Chongqing Medical University,
Chongqing 400016, PR China.
The oncogenic BCR/ABL tyrosine kinase induces constitutive enhanced
"spontaneous" DNA damage and unfaithful repair in Philadelphia chromosome
positive leukemia cells. Here, we investigated the changes of protein profile in
H2O2-induced DNA damage/repair in BaF3-MIGR1 and BaF3-BCR/ABL cells through a
proteomic strategy consisting of two-dimensional gel electrophoresis (2-DE)
coupled with MALDI-TOF mass spectrometry. In total, 41 spots were differentially
expressed and 13 proteins were identified with further MS analysis. Two
essential proteins, Proto-oncogene tyrosine-protein kinase ABL1 (c-ABL) and Heat
shock 70kDa protein 4 (Apg-2), were confirmed by Western blot and showed
consistent changes with proteomic results. Moreover, functional analysis
demonstrated that inhibition of Apg-2 not only decreased cell proliferation, but
also induced cell apoptosis in BCR/ABL positive cells (BaF3-BCR/ABL,
BaF3-BCR/ABL(T315I)). We also proved that Apg-2 inhibition aggravated H2O2
induced damage in BCR/ABL positive cells, and enhanced the sensitivity of
BaF3-BCR/ABL(T315I) to STI571. Taken together, the findings in this work provide
us with some clues to a better understanding of the molecular mechanisms
underlying BCR/ABL in the DNA damage/repair processes and demonstrated that
Apg-2 would be a valid target for anti-leukemia drug development.
© 2013.
DOI: 10.1016/j.cellsig.2013.08.023
PMID: 24012954 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22662734 | 1. Psychol Serv. 2012 May;9(2):200-202. doi: 10.1037/a0025987.
Tele-pain management: use of videoconferencing technology in the delivery of an
integrated cognitive-behavioral and physical therapy group intervention.
Palyo SA(1), Schopmeyer KA(2), McQuaid JR(1).
Author information:
(1)Mental Health Service, San Francisco VA Medical Center.
(2)Neurology and Rehabilitation Service, San Francisco VA Medical Center.
Chronic pain has been recognized as a highly prevalent problem, and
interdisciplinary treatments have been shown to be effective in the treatment of
chronic pain. An integrated cognitive-behavioral and physical therapy group
protocol has been developed and then implemented at remote sites using
videoconferencing technology to provide pain management for veterans. The
treatment model is summarized and recommendations are made for addressing
challenges in implementing this type of treatment via videoconferencing.
DOI: 10.1037/a0025987
PMID: 22662734 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19191503 | 1. Biochemistry. 2009 Mar 24;48(11):2411-21. doi: 10.1021/bi8021526.
Phospholamban modulates the functional coupling between nucleotide domains in
Ca-ATPase oligomeric complexes in cardiac sarcoplasmic reticulum.
Chen LT(1), Yao Q, Soares TA, Squier TC, Bigelow DJ.
Author information:
(1)Biological Sciences Division, Pacific Northwest National Laboratory, P.O. Box
999, Richland, Washington 99352, USA.
Oligomeric interactions between Ca-ATPase polypeptide chains and their
modulation by phospholamban (PLB) were measured in native cardiac sarcoplasmic
reticulum (SR) microsomes. Progressive modification of Lys(514) with fluorescein
5-isothiocyanate (FITC), which physically blocks access to the nucleotide
binding site by ATP, demonstrates that Ca-ATPase active sites function
independently of one another prior to the phosphorylation of PLB. However, upon
cAMP-dependent protein kinase (PKA) phosphorylation of PLB, a second-order
dependence between residual enzyme activity and the fraction of active sites is
observed, consistent with a dimeric functional complex. Complementary distance
measurements were made using FITC or 5-iodoacetamidofluorescein (IAF) bound to
Cys(674) within the N- or P-domains, respectively, to detect structural coupling
within oligomeric complexes. Accompanying the phosphorylation of PLB,
neighboring Ca-ATPase polypeptide chains exhibit a 4 +/- 2 A decrease in the
proximity between FITC sites within the N-domain and a 9 +/- 3 A increase in the
proximity between IAF sites within P-domains. Thus, the phosphorylation of PLB
induces spatial rearrangements between the N- and P-domain elements of proximal
Ca-ATPase polypeptide chains which restore functional interactions between
neighboring polypeptide chains and, in turn, result in increased rates of
catalytic turnover. These results are interpreted in terms of a structural
model, calculated through optimization of shape complementarity, desolvation,
and electrostatic energies, which suggests a dimeric arrangement of Ca-ATPase
polypeptide chains through the proximal association of N-domains that
accommodates interaction with PLB. We suggest that the phosphorylation of PLB
acts to release constraints involving interdomain subunit interactions that
enhance catalytically important N-domain motions.
DOI: 10.1021/bi8021526
PMCID: PMC2765579
PMID: 19191503 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7857766 | 1. Cell Signal. 1994 Aug;6(6):617-30. doi: 10.1016/0898-6568(94)90045-0.
Phosphorylation of phospholamban in aortic smooth muscle cells and heart by
calcium/calmodulin-dependent protein kinase II.
Chen W(1), Lah M, Robinson PJ, Kemp BE.
Author information:
(1)St Vincent's Institute of Medical Research, Fitzroy, Vic., Australia.
Phospholamban is a negative regulator of the sarcoplasmic reticulum
Ca(2+)-pumping ATPase. Phosphorylation of phospholamban activates the ATPase and
decreases the level of cytosolic calcium. Phospholamban is phosphorylated in
heart by cAMP-dependent protein kinase, cGMP-dependent protein kinase and
calcium/calmodulin-dependent protein kinase II (CM-kinase-II) and in smooth
muscle cells by cGMP-dependent protein kinase. In contrast to heart muscle,
phospholamban is poorly phosphorylated by CM-kinase-II in extracts of rat aortic
smooth muscle cells. Rat aorta phospholamban amino acid sequence was identical
to dog heart. The peptide substrate specificity of CM-kinase-II from rat aorta
was the same as that from rat heart. The lack of phosphorylation of rat aorta
phospholamban by the CM-kinase-II appears to result from the relatively low
abundance of phospholamban in smooth muscle.
DOI: 10.1016/0898-6568(94)90045-0
PMID: 7857766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15229104 | 1. Am J Physiol Cell Physiol. 2004 Nov;287(5):C1202-8. doi:
10.1152/ajpcell.00155.2004. Epub 2004 Jun 30.
Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated
with impaired SR function and regulation.
Babick AP(1), Cantor EJ, Babick JT, Takeda N, Dhalla NS, Netticadan T.
Author information:
(1)Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, Winnipeg, Manitoba, Canada R2H 2A6.
Although dilated cardiomyopathy (DCM) is known to result in cardiac contractile
dysfunction, the underlying mechanisms are unclear. The sarcoplasmic reticulum
(SR) is the main regulator of intracellular Ca2+ required for cardiac
contraction and relaxation. We therefore hypothesized that abnormalities in both
SR function and regulation will contribute to cardiac contractile dysfunction of
the J2N-k cardiomyopathic hamster, an appropriate model of DCM.
Echocardiographic assessment indicated contractile dysfunction, because the
ejection fraction, fractional shortening, cardiac output, and heart rate were
all significantly reduced in J2N-k hamsters compared with controls. Depressed
cardiac function was associated with decreased cardiac SR Ca2+ uptake in the
cardiomyopathic hamsters. Reduced SR Ca2+ uptake could be further linked to a
decrease in the expression of the SR Ca(2+)-ATPase and cAMP-dependent protein
kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16.
Depressed PLB phosphorylation was paralleled with a reduction in the activity of
SR-associated PKA, as well as an elevation in protein phosphatase activity in
J2N-k hamster. The results of this study suggest that an alteration in SR
function and its regulation contribute to cardiac contractile dysfunction in the
J2N-k cardiomyopathic hamster.
DOI: 10.1152/ajpcell.00155.2004
PMID: 15229104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16530877 | 1. J Hepatol. 2006 Jul;45(1):5-12. doi: 10.1016/j.jhep.2005.12.020. Epub 2006 Feb
3.
HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease
expression of Bach1 in human hepatoma cells.
Ghaziani T(1), Shan Y, Lambrecht RW, Donohue SE, Pietschmann T, Bartenschlager
R, Bonkovsky HL.
Author information:
(1)Department of Medicine, University of Connecticut Health Center, 263
Farmington Avenue, Farmington, CT 06030-1111, USA.
BACKGROUND/AIMS: Hepatitis C infection induces hepatic oxidative stress. Heme
oxygenase (HO), the rate-controlling enzyme of heme catabolism, plays a key role
as a protector against oxidative, and other stresses. Other recent work has
implicated Bach1, a heme binding protein that represses gene expression, in the
regulation of HO-1 gene expression.
METHODS: We investigated the effects of HCV polyprotein expression on expression
of HO-1 and Bach1 genes in human hepatoma cells (Huh-7 cells).
RESULTS: HO-1 was up-regulated in the cell line expressing HCV proteins from
core up to the aminoterminal domain of NS3. Addition of increasing
concentrations of N-acetylcysteine (NAC) led to down-regulation of HO-1 in cells
expressing HCV proteins. In contrast, Bach1 was significantly down-regulated in
these cells. Sodium arsenite, a strong inducer of oxidative stress and HO-1,
reduced Bach1 expression in wild type Huh-7 cells, and NAC partially abrogated
this decrease.
CONCLUSIONS: Huh-7 cells expressing HCV proteins show significant up-regulation
of the HO-1 gene, and reciprocal down-regulation of the Bach1 gene. Exogenous
oxidative stressors and anti-oxidants can modulate expression of these genes.
These and other results suggest a key role of down-regulation of Bach1 and
up-regulation of HO-1 in diminishing cytotoxic effects of HCV proteins in human
hepatocytes.
DOI: 10.1016/j.jhep.2005.12.020
PMID: 16530877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9886310 | 1. Br J Haematol. 1998 Dec;103(4):990-6. doi: 10.1046/j.1365-2141.1998.01103.x.
Dyskeratosis Congenita (DC) Registry: identification of new features of DC.
Knight S(1), Vulliamy T, Copplestone A, Gluckman E, Mason P, Dokal I.
Author information:
(1)Department of Haematology, Imperial College School of Medicine, London, UK.
Comment in
Br J Haematol. 1999 May;105(2):571. doi: 10.1111/j.1365-2141.1999.01437.x.
Dyskeratosis congenita (DC) is an inherited disorder characterized by skin
pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis
Congenita Registry was established at the Hammersmith Hospital. In the 46
families recruited, 76/83 patients were male, suggesting that the major form of
DC is X-linked. As well as a variety of noncutaneous abnormalities, the majority
(93%) of patients had bone marrow (BM) failure and this was the principal cause
(71%) of early mortality. In addition to BM hypoplasia, some patients also
developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities
were present in 19% of patients. In affected females the phenotype was less
severe. Some female carriers of X-linked DC had clinical features. Carriers of
X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting
that cells expressing the normal DC allele have a growth/survival advantage over
cells that express the mutant allele. Linkage analysis in multiplex families
confirmed that the DKC1 gene, responsible for the X-linked form of DC, is
located within Xq28 and facilitated its positional cloning. The high incidence
of BM failure in association with a wide range of somatic abnormalities together
with the ubiquitous expression of DKC1 suggest that, as well as having a
critical role in normal haemopoiesis, this gene has a key role in normal cell
biology.
DOI: 10.1046/j.1365-2141.1998.01103.x
PMID: 9886310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19565475 | 1. Arthritis Rheum. 2009 Jul;60(7):1895-905. doi: 10.1002/art.24567.
The safety and efficacy of a JAK inhibitor in patients with active rheumatoid
arthritis: Results of a double-blind, placebo-controlled phase IIa trial of
three dosage levels of CP-690,550 versus placebo.
Kremer JM(1), Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D,
Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH.
Author information:
(1)Albany Medical College, Albany, New York, USA.
Erratum in
Arthritis Rheum. 2012 May;64(5):1487.
Comment in
Curr Rheumatol Rep. 2011 Oct;13(5):379-80. doi: 10.1007/s11926-011-0196-4.
OBJECTIVE: To determine the efficacy, safety, and tolerability of 3 different
dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with
active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab,
or adalimumab caused an inadequate or toxic response.
METHODS: Patients (n = 264) were randomized equally to receive placebo, 5 mg of
CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks,
and were followed up for an additional 6 weeks after treatment. The primary
efficacy end point was the American College of Rheumatology 20% improvement
criteria (ACR20) response rate at 6 weeks.
RESULTS: By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the
5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in
the placebo group (P < 0.001). Improvements in disease activity in
CP-690,550-treated patients compared with placebo were seen in all treatment
groups as early as week 1. ACR50 and ACR70 response rates significantly improved
in all treatment groups by week 4. The most common adverse events reported were
headache and nausea. The infection rate in both the 15 mg twice daily group and
the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No
opportunistic infections or deaths occurred. Increases in mean low-density
lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and
increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all
CP-690,550 treatment arms.
CONCLUSION: Our findings indicate that CP-690,550 is efficacious in the
treatment of RA, resulting in rapid, statistically significant, and clinically
meaningful reductions in the signs and symptoms of RA. Further studies of
CP-690,550 in RA are warranted.
DOI: 10.1002/art.24567
PMID: 19565475 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18989882 | 1. Pediatr Blood Cancer. 2009 Mar;52(3):376-8. doi: 10.1002/pbc.21813.
NOLA1 gene mutations in acquired aplastic anemia.
Pigullo S(1), Pavesi E, Dianzani I, Santamaria G, Svahn J, Risso M, Van Lint MT,
Pillon M, Iori AP, Longoni D, Ramenghi U, Lanciotti M, Dufour C.
Author information:
(1)Hematology Unit, G. Gaslini Children Hospital, Genova, Italy.
Comment in
Pediatr Blood Cancer. 2009 May;52(5):687. doi: 10.1002/pbc.21903.
BACKGROUND: Telomerase complex genes mutations (DKC1, TERC, TERT, and NOP10)
lead to premature telomere shortening and are responsible for different forms of
dyskeratosis congenita. TERC and TERT mutations were also found in patients with
aplastic anemia. The aim of this work is to analyze the possible involvement of
the telomerase complex gene NOLA1, in a population of Italian AA patients.
PROCEDURE: DNA of 108 AA patients and 170 normal controls was amplified by PCR
and analyzed by DHPLC. For each abnormal elution profile PCR products was
directly sequenced using ABI prism 3100 Genetic Analyzer.
RESULTS: We identified, in two patients and two control, the new c.390A > T
variation, which is not reported in GenBank, and leads to p.H28L amino acidic
change. Telomere analysis shows that the subjects carrying the change have a
telomere length comparable to that of healthy controls thus suggesting that this
variation has no effect on telomerase complex activity.
CONCLUSIONS: We did not find any clear disruptive mutation in NOLA1 gene. The
non-conservative variation identified in our sample has no effect on telomeres
length. This result suggests that heterozygous point mutations in NOLA1 gene are
not responsible for AA in our patients at least acting via telomere. However, in
our experience, molecular analysis of other telomerase complex gene (TERC, TERT)
is important for AA patients and family members in order to set up an adequate
therapeutic or surveillance program and identify carriers or exclude them as
potential bone marrow donors.
DOI: 10.1002/pbc.21813
PMID: 18989882 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1691523 | 1. Res Virol. 1990 Jan-Feb;141(1):31-43. doi: 10.1016/0923-2516(90)90054-m.
Effects of human recombinant alpha and gamma and of highly purified natural beta
interferons on simian Spumavirinae prototype (simian foamy virus 1)
multiplication in human cells.
Rhodes-Feuillette A(1), Lasneret J, Paulien S, Ogunkolade W, Periés J, Canivet
M.
Author information:
(1)Immunomodulation Laboratory, Hôpital Saint-Louis, Paris.
The present study demonstrates the inhibitory effect of human recombinant
interferons (r-Hu-IFN) alpha and gamma, and that of highly purified natural
human interferon beta on the replication of simian foamy virus type 1 (SFV1) in
human AV3-cell cultures. All IFN led to strong inhibition of the SFV1 cytopathic
effect. Electron microscopy showed a 70 to 95% decrease in viral particles.
Significant inhibition of virus-associated reverse transcriptase activity was
found in supernatant fluids of infected IFN-treated cultures. Metabolic
labelling of the virus confirmed the inhibition of extracellular release of
SFV1. PAGE analysis of immunoprecipitates indicated a reduction in
viral-specific protein bands. Altogether, these results indicate that the
mechanism of inhibition of Spumavirinae infection by interferon differs from
that described for the other Retroviridae, and particularly for types B, C and D
viruses. Our data is of therapeutic interest since Spumavirinae have been linked
to pathological processes such as de Quervain thyroiditis.
DOI: 10.1016/0923-2516(90)90054-m
PMID: 1691523 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18555605 | 1. Neurosci Lett. 2008 Aug 1;440(2):160-5. doi: 10.1016/j.neulet.2008.04.082.
Epub 2008 Apr 26.
Regulation of heme oxygenase-1 by transcription factor Bach1 in the mouse brain.
Sakoda E(1), Igarashi K, Sun J, Kurisu K, Tashiro S.
Author information:
(1)Department of Neurosurgery, Graduate School of Biomedical Sciences, Hiroshima
University, Japan. [email protected]
Oxidative stress has been implicated in tissue damage from traumatic brain
injury. Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades prooxidant
heme to radical-scavenging biliverdin/bilirubin in order to protect cells from
oxidative stress. Although HO-1 is induced after induction of brain damage, the
regulatory mechanism of HO-1 in the brain is still unclear. Bach1 is a
transcriptional repressor of the HO-1 gene, and plays a critical role in tissue
protection from oxidative stress by reperfusion injury of the myocardium. In
this study, we examined the role of Bach1 in HO-1 regulation of the various
brain sites by investigating the expression of Bach1 and HO-1 in brain tissues
of mice bearing Bach1-deficient (Bach1(-/-)) or wild-type (Bach1(+/+)) genes.
While the expression levels of Bach1 mRNA in the olfactory bulb were
significantly higher than other brain areas, those at the cortex showed the
lowest activity. Bach1(-/-) mice showed significantly higher HO-1 mRNA
expression levels than Bach1(+/+) mice in all brain sites studied. Moreover,
higher induction of HO-1 was observed around damaged tissues after cold injury
in Bach1(-/-) than Bach1(+/+) mice. Thus, Bach1 plays an important role in
regulating the constitutive and inducible expression levels of HO-1 in the
brain. Although a significantly higher level of HO-1 was observed in Bach1(-/-)
than Bach1(+/+) mice, genetic ablation of the Bach1 gene failed to show any
tissue protective effect after cold injury was inflicted on the cortex.
DOI: 10.1016/j.neulet.2008.04.082
PMID: 18555605 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24504254 | 1. G3 (Bethesda). 2014 Apr 16;4(4):613-22. doi: 10.1534/g3.114.010470.
Edc3 function in yeast and mammals is modulated by interaction with NAD-related
compounds.
Walters RW(1), Shumilin IA, Yoon JH, Minor W, Parker R.
Author information:
(1)Department Chemistry and Biochemistry, University of Colorado, Boulder,
Colorado.
The control of mRNA translation and degradation is mediated in part by a set of
proteins that can inhibit translation and promote decapping, as well as function
in the assembly of cytoplasmic mRNP granules referred to as processing bodies
(P-bodies). The conserved enhancer of mRNA decapping 3 (Edc3) protein functions
to promote both decapping and P-body assembly. Crystal structures of the YjeF_N
domain in hEdc3 identified a putative binding site for a small molecule.
Structure modeling of the human Edc3 Yjef_N along with other Yjef_N-containing
proteins suggests that this molecule is related to NAD(H). We now show human
Edc3 directly binds NADH. We also show that human and yeast Edc3 chemically
modify NAD in vitro. Mutations that are predicted to disrupt the binding and/or
hydrolysis of an NAD-related molecule by yeast and human Edc3 affect the control
of mRNA degradation and/or P-body composition in vivo. This suggests that the
interaction of Edc3 with an NAD-related molecule affects its function in the
regulation of mRNA translation and degradation and provides a possible mechanism
to couple the energetics of the cell to posttranscriptional control. Moreover,
this provides a unique example of and lends strength to the postulated
connection of metabolites, enzymes, and RNA.
DOI: 10.1534/g3.114.010470
PMCID: PMC4059234
PMID: 24504254 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21375412 | 1. Telemed J E Health. 2011 Apr;17(3):211-6. doi: 10.1089/tmj.2010.0136. Epub
2011 Mar 5.
Technology-mediated therapy for chronic pain management: the challenges of
adapting behavior change interventions for delivery with pervasive communication
technology.
Rosser BA(1), McCullagh P, Davies R, Mountain GA, McCracken L, Eccleston C.
Author information:
(1)Centre for Pain Research, The University of Bath, Bath, United Kingdom.
OBJECTIVE: Adapting therapeutic practice from traditional face-to-face exchange
to remote technology-based delivery presents challenges for the therapist,
patient, and technical writer. This article documents the process of therapy
adaptation and the resultant specification for the SMART2 project-a
technology-based self-management system for assisting long-term health
conditions, including chronic pain.
MATERIALS AND METHODS: Focus group discussions with healthcare professionals and
patients were conducted to inform selection of therapeutic objectives and
appropriate technology.
RESULTS: Pertinent challenges are identified, relating to (1) reduction and
definition of therapeutic objectives, and (2) how to approach adaptation of
therapy to a form suited to technology delivery. The requirement of the system
to provide dynamic and intelligent responses to patient experience and behavior
is also emphasized.
CONCLUSION: Solutions to these challenges are described in the context of the
SMART2 technology-based intervention. More explicit discussion and documentation
of therapy adaptation to technology-based delivery within the literature is
encouraged.
DOI: 10.1089/tmj.2010.0136
PMID: 21375412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24286424 | 1. Chin Med J (Engl). 2013 Dec;126(23):4552-6.
Demethylating agent decitabine induces autologous cancer testis antigen specific
cytotoxic T lymphocytes in vivo.
Zhou JH(1), Yao YS, Wang LX, Wang J, Li YH, Jiang MM, Zhou MH, Gao XN, Li RS,
Wang LL, Yu L.
Author information:
(1)Department of Hematology, Chinese People's Liberation Army General Hospital,
Beijing 100853, China.
BACKGROUND: Cancer testis antigens (CTAs) are a novel group of tumor associated
antigens. Demethylating agent decitabine was reported to be able to up-regulate
CTAs through its hypomethylation mechanism, thus enhance the immunogenicity of
leukemia cells. However, few researches have ever focused on the questions that
whether this immunostimulatory effect of decitabine could induce autologous CTA
specific cytotoxic T lymphocytes (CTLs) in vivo, and if so, whether this effect
contributes to disease control. In this study, we aimed to show that decitabine
could induce specific autologous CTLs against some mouse CTAs in leukemia cells
in vitro and in vivo.
METHODS: Several mouse CTAs were screened by RT-PCR. CTL specific to one of the
CTAs named P1A was detected and sorted by P1A specific dimer by flow cytometry.
The activity of specific CTLs was measured by real time RT-PCR.
RESULTS: We firstly screened expression of some CTAs in mouse leukemia cells
before and after decitabine treatment and found that decitabine treatment did
up-regulate expression of many CTAs. Then we measured the CTLs' activity
specific to a mouse CTA P1A in vivo and showed that this activity increased
after decitabine treatment. Finally, we sorted these in vivo induced P1A
specific CTLs by flow cytometry and demonstrated their cytotoxicity against
decitabine treated leukemia cells.
CONCLUSIONS: Our study showed the autologous immune response induced by
decitabine in vivo. And more importantly, we firstly proved that this response
may contribute to disease control. We believe that this immunostimulatory effect
is another anti-cancer mechanism of decitabine, and this special effect would
inspire new applications of decitabine in the field of leukemia treatment in the
future.
PMID: 24286424 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21215266 | 1. Dev Biol. 2011 Mar 1;351(1):135-45. doi: 10.1016/j.ydbio.2010.12.043. Epub
2011 Jan 4.
Functional analysis of Rfx6 and mutant variants associated with neonatal
diabetes.
Pearl EJ(1), Jarikji Z, Horb ME.
Author information:
(1)Laboratory of Molecular Organogenesis, Institut de recherches cliniques de
Montréal, 110 avenue des Pins Ouest, Montreal, QC H2V4K1, Canada.
[email protected]
Mutations in rfx6 were recently associated with Mitchell-Riley syndrome, which
involves neonatal diabetes, and other digestive system defects. To better define
the function of Rfx6 in early endoderm development we cloned the Xenopus
homologue. Expression of rfx6 begins early, showing broad expression throughout
the anterior endoderm; at later stages rfx6 expression becomes restricted to the
endocrine cells of the gut and pancreas. Morpholino knockdown of rfx6 caused a
loss of pancreas marker expression, as well as other abnormalities. Co-injection
of exogenous wild-type rfx6 rescued the morpholino phenotype in Xenopus
tadpoles, whereas attempts to rescue the loss-of-function phenotype using mutant
rfx6 based on Mitchell-Riley patients were unsuccessful. To better define the
pleiotropic effects, we performed microarray analyses of gene expression in
knockdown foregut tissue. In addition to pancreatic defects, the microarray
analyses revealed downregulation of lung, stomach and heart markers and an
upregulation of kidney markers. We verified these results using RT-PCR and in
situ hybridization. Based on the different rfx6 expression patterns and our
functional analyses, we propose that rfx6 has both early and late functions. In
early development Rfx6 plays a broad role, being essential for development of
most anterior endodermal organs. At later stages however, Rfx6 function is
restricted to endocrine cells.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ydbio.2010.12.043
PMCID: PMC3042741
PMID: 21215266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21940714 | 1. J Biomol Screen. 2012 Jan;17(1):49-58. doi: 10.1177/1087057111416659. Epub
2011 Sep 21.
Development of homogeneous nonradioactive methyltransferase and demethylase
assays targeting histone H3 lysine 4.
Gauthier N(1), Caron M, Pedro L, Arcand M, Blouin J, Labonté A, Normand C,
Paquet V, Rodenbrock A, Roy M, Rouleau N, Beaudet L, Padrós J, Rodriguez-Suarez
R.
Author information:
(1)PerkinElmer,1744 William Street, Suite 600, Montreal, Quebec, Canada, H3J
1R4.
Histone posttranslational modifications are among the epigenetic mechanisms that
modulate chromatin structure and gene transcription. Histone methylation and
demethylation are dynamic processes controlled respectively by histone
methyltransferases (HMTs) and demethylases (HDMs). Several HMTs and HDMs have
been implicated in cancer, inflammation, and diabetes, making them attractive
targets for drug therapy. Hence, the discovery of small-molecule modulators for
these two enzyme classes has drawn significant attention from the pharmaceutical
industry. Herein, the authors describe the development and optimization of
homogeneous LANCE Ultra and AlphaLISA antibody-based assays for measuring the
catalytic activity of two epigenetic enzymes acting on lysine 4 of histone H3:
SET7/9 methyltransferase and LSD1 demethylase. Both the SET7/9 and LSD1 assays
were designed as signal-increase assays using biotinylated peptides derived from
the N-terminus of histone H3. In addition, the SET7/9 assay was demonstrated
using full-length histone H3 protein as substrate in the AlphaLISA format.
Optimized assays in 384-well plates are robust (Z' factors ≥0.7) and sensitive,
requiring only nanomolar concentrations of enzyme and substrate. All assays
allowed profiling of known SET7/9 and LSD1 inhibitors. The results demonstrate
that the optimized LANCE Ultra and AlphaLISA assay formats provide a relevant
biochemical screening approach toward the identification of small-molecule
inhibitors of HMTs and HDMs that could lead to novel epigenetic therapies.
DOI: 10.1177/1087057111416659
PMID: 21940714 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11059665 | 1. J Neurosurg. 2000 Nov;93(5):829-34. doi: 10.3171/jns.2000.93.5.0829.
Improvement in mitochondrial dysfunction as a new surrogate efficiency measure
for preclinical trials: dose-response and time-window profiles for
administration of the calcium channel blocker Ziconotide in experimental brain
injury.
Verweij BH(1), Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP.
Author information:
(1)Department of Neurosurgery, University of California at Davis Medical Center,
Sacramento 95817, USA.
OBJECT: Determining the efficacy of a drug used in experimental traumatic brain
injury (TBI) requires the use of one or more outcome measures such as decreased
mortality or fewer neurological and neuropsychological deficits. Unfortunately,
outcomes in these test batteries have a fairly large variability, requiring
relatively large sample sizes, and administration of the tests themselves is
also very time consuming. The authors previously demonstrated that experimental
TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial
dysfunction is easy to assess compared with neurobehavioral endpoints, it might
prove useful as an outcome measure to establish therapeutic time windows and
dose-response curves in preclinical drug testing. This idea was tested in a
model of TBI in rats.
METHODS: Animals treated with the selective N-type voltage-sensitive calcium
channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical
impact displayed significant improvement in brain mitochondrial function. When a
single intravenous bolus injection of 4 mg/kg Ziconotide was given at different
time intervals, ranging from 15 minutes before injury to 10 hours after injury,
mitochondrial function was improved at all time points, but more so between 2
and 6 hours postinjury. The authors evaluated the effects on mitochondrial
function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a
single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum
dose.
CONCLUSIONS: The authors established these time-window profiles and
dose-response curves on the basis of mitochondrial outcome measures in a total
of 42 rats because there were such low standard deviations in these tests.
Establishing similar time-window profiles and dose-response curves by using
neurobehavioral endpoints would have required using 114 rats in much more
elaborate experiments.
DOI: 10.3171/jns.2000.93.5.0829
PMID: 11059665 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17399643 | 1. Heart Rhythm. 2007 Apr;4(4):512-5. doi: 10.1016/j.hrthm.2006.10.030. Epub 2006
Nov 10.
Electrophysiologic characteristics of an Andersen syndrome patient with KCNJ2
mutation.
Nagase S(1), Kusano KF, Yoshida M, Ohe T.
Author information:
(1)Department of Cardiovascular Medicine, Okayama University Graduate School of
Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
[email protected] <[email protected]>
We report the first case of a patient with Andersen syndrome in whom
electrophysiologic study was performed. The patient was a 19-year-old woman with
familial periodic paralysis, abnormal QT-U complex, and nonsustained ventricular
tachycardia. Mutation analysis revealed a missense mutation in KCNJ2, a
component of Kir2.1. Monophasic action potential recordings showed a delayed
afterdepolarization (DAD)-like hump in the left ventricle. Initiation of
epinephrine-induced premature ventricular contractions always coincided with
both the exaggerated DAD-like hump and the U wave. These findings suggest that
reduced Kir2.1 current contributes to the development of DAD and ventricular
arrhythmias in Andersen syndrome.
DOI: 10.1016/j.hrthm.2006.10.030
PMID: 17399643 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10327208 | 1. Neurosci Lett. 1999 Apr 9;265(1):67-9. doi: 10.1016/s0304-3940(99)00208-6.
Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological
feature revealed by alpha-synuclein immunocytochemistry.
Braak H(1), Sandmann-Keil D, Gai W, Braak E.
Author information:
(1)Department of Anatomy, J.W. Goethe University, Frankfurt/Main, Germany.
[email protected]
Lewy bodies and coarse Lewy neurites are the pathological hallmarks of
degenerating neurons in the brains of patients suffering from Parkinson's
disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be
a major component of Lewy bodies and Lewy neurites. This study demonstrates for
the first time that extensive and thin alpha-synuclein-immunoreactive inclusions
are present in the axonal processes of neurons.
DOI: 10.1016/s0304-3940(99)00208-6
PMID: 10327208 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24209455 | 1. BMC Bioinformatics. 2013 Nov 9;14:320. doi: 10.1186/1471-2105-14-320.
Design of RNA splicing analysis null models for post hoc filtering of Drosophila
head RNA-Seq data with the splicing analysis kit (Spanki).
Sturgill D(1), Malone JH, Sun X, Smith HE, Rabinow L, Samson ML, Oliver B.
Author information:
(1)National Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, 50 South Drive, Bethesda, MD 20892, USA.
[email protected].
BACKGROUND: The production of multiple transcript isoforms from one gene is a
major source of transcriptome complexity. RNA-Seq experiments, in which
transcripts are converted to cDNA and sequenced, allow the resolution and
quantification of alternative transcript isoforms. However, methods to analyze
splicing are underdeveloped and errors resulting in incorrect splicing calls
occur in every experiment.
RESULTS: We used RNA-Seq data to develop sequencing and aligner error models. By
applying these error models to known input from simulations, we found that
errors result from false alignment to minor splice motifs and antisense stands,
shifted junction positions, paralog joining, and repeat induced gaps. By using a
series of quantitative and qualitative filters, we eliminated diagnosed errors
in the simulation, and applied this to RNA-Seq data from Drosophila melanogaster
heads. We used high-confidence junction detections to specifically interrogate
local splicing differences between transcripts. This method out-performed
commonly used RNA-seq methods to identify known alternative splicing events in
the Drosophila sex determination pathway. We describe a flexible software
package to perform these tasks called Splicing Analysis Kit (Spanki), available
at http://www.cbcb.umd.edu/software/spanki.
CONCLUSIONS: Splice-junction centric analysis of RNA-Seq data provides
advantages in specificity for detection of alternative splicing. Our software
provides tools to better understand error profiles in RNA-Seq data and improve
inference from this new technology. The splice-junction centric approach that
this software enables will provide more accurate estimates of differentially
regulated splicing than current tools.
DOI: 10.1186/1471-2105-14-320
PMCID: PMC3827500
PMID: 24209455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16585166 | 1. Cancer Res. 2006 Apr 1;66(7):3443-51. doi: 10.1158/0008-5472.CAN-05-3739.
A single nucleotide polymorphism chip-based method for combined genetic and
epigenetic profiling: validation in decitabine therapy and tumor/normal
comparisons.
Yuan E(1), Haghighi F, White S, Costa R, McMinn J, Chun K, Minden M, Tycko B.
Author information:
(1)Institute for Cancer Genetics, Columbia University Medical Center, 1150 St.
Nicholas Avenue, New York, NY 10032, USA.
Progress on several unresolved issues in cancer epigenetics will benefit from
rapid and standardized methods for profiling DNA methylation genome-wide. In the
area of epigenetic therapy, the demethylating drug decitabine
(5-aza-2'-deoxycytidine) is increasingly used to treat acute myelogenous
leukemia and myelodysplastic syndrome, but the mechanisms of its anticancer
activity have remained unclear. Given the clinical efficacy of decitabine and
the uncertainties about its mode of action, it will be useful to optimize
methods for following DNA methylation as a biochemical response in individual
patients. Here, we describe a single nucleotide polymorphism (SNP) chip-based
method (MSNP) for profiling DNA methylation. Using this procedure, the extent of
demethylation in bone marrow aspirates from patients with leukemia receiving
decitabine can be assessed genome-wide using commercially available (Affymetrix)
SNP chips. We validated the accuracy of MSNP by comparing the results with
combined bisulfite restriction analysis and by sequencing cloned PCR products
from bisulfite-converted DNA. We further validated MSNP in a Wilms' tumor/normal
kidney comparison, comparing the results with methylation-sensitive Southern
blotting. MSNP simultaneously detects aberrations in DNA copy number and loss of
heterozygosity, making it a generally useful approach for combined genetic and
epigenetic profiling in tissue samples from cancer patients.
DOI: 10.1158/0008-5472.CAN-05-3739
PMID: 16585166 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23155066 | 1. Nucleic Acids Res. 2013 Jan;41(2):e39. doi: 10.1093/nar/gks1026. Epub 2012 Nov
15.
DiffSplice: the genome-wide detection of differential splicing events with
RNA-seq.
Hu Y(1), Huang Y, Du Y, Orellana CF, Singh D, Johnson AR, Monroy A, Kuan PF,
Hammond SM, Makowski L, Randell SH, Chiang DY, Hayes DN, Jones C, Liu Y, Prins
JF, Liu J.
Author information:
(1)Department of Computer Science, University of Kentucky, Lexington, KY 40506,
USA.
The RNA transcriptome varies in response to cellular differentiation as well as
environmental factors, and can be characterized by the diversity and abundance
of transcript isoforms. Differential transcription analysis, the detection of
differences between the transcriptomes of different cells, may improve
understanding of cell differentiation and development and enable the
identification of biomarkers that classify disease types. The availability of
high-throughput short-read RNA sequencing technologies provides in-depth
sampling of the transcriptome, making it possible to accurately detect the
differences between transcriptomes. In this article, we present a new method for
the detection and visualization of differential transcription. Our approach does
not depend on transcript or gene annotations. It also circumvents the need for
full transcript inference and quantification, which is a challenging problem
because of short read lengths, as well as various sampling biases. Instead, our
method takes a divide-and-conquer approach to localize the difference between
transcriptomes in the form of alternative splicing modules (ASMs), where
transcript isoforms diverge. Our approach starts with the identification of ASMs
from the splice graph, constructed directly from the exons and introns predicted
from RNA-seq read alignments. The abundance of alternative splicing isoforms
residing in each ASM is estimated for each sample and is compared across sample
groups. A non-parametric statistical test is applied to each ASM to detect
significant differential transcription with a controlled false discovery rate.
The sensitivity and specificity of the method have been assessed using simulated
data sets and compared with other state-of-the-art approaches. Experimental
validation using qRT-PCR confirmed a selected set of genes that are
differentially expressed in a lung differentiation study and a breast cancer
data set, demonstrating the utility of the approach applied on experimental
biological data sets. The software of DiffSplice is available at
http://www.netlab.uky.edu/p/bioinfo/DiffSplice.
DOI: 10.1093/nar/gks1026
PMCID: PMC3553996
PMID: 23155066 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16211386 | 1. Ann Hematol. 2005 Dec;84 Suppl 1:9-17. doi: 10.1007/s00277-005-0012-1.
An epigenetic approach to the treatment of advanced MDS; the experience with the
DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients.
Wijermans PW(1), Lübbert M, Verhoef G, Klimek V, Bosly A.
Author information:
(1)Department of Haematology, Leyenburg Hospital, The Hague, The Netherlands.
[email protected]
During the last 10 years, three European phase II studies were performed to
investigate the treatment of elderly patients with myelodysplastic syndrome
(MDS) with low-dose 5-aza-2'-deoxycytidine (decitabine, DAC). All these European
trial data were reviewed on the basis of the International Prognostic Scoring
System (IPSS) risk criteria and the response criteria as recently published by
an international working group. To investigate the results in a larger cohort of
patients and to determine risk factors, all data were pooled with some
observations from the PCH 95-06 US phase II study. The response rate in the 177
patients evaluated (median age 70 years) was 49%. The median response duration
was 36 weeks, and the median survival was 15 months. Analysis of the data
according to sex, age, French-American-British classification, percentage of
blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and
cytogenetics did not reveal any factor predictive of response. Overall, 69% of
patients benefited, including those with stable disease during therapy. Response
duration was significantly shorter with increasing risk (according to the IPSS
classification). Haemoglobin level and neutrophil count showed an inverse
correlation to the IPSS classification. Univariate analysis showed a
significantly inferior survival for elderly patients (>75 years of age) and for
those with high levels of serum lactate dehydrogenase (LDH) (more than two times
the normal values). Patients with high-risk cytogenetic abnormalities according
to the IPSS risk criteria showed better overall survival than those with
intermediate-risk abnormalities. When analysed according to the IPSS risk
classification, high-risk patients had worse survival prospects following
decitabine therapy than those with intermediate risk; however, compared to the
originally reported IPPS outcomes for high-risk patients, they probably showed
better survival. During the treatment period, 18% of the patients progressed
towards acute leukaemia. Decitabine showed a rather low toxicity profile in this
elderly patient group. In conclusion, low-dose decitabine is an active drug for
the treatment of MDS patients, even for those older than 75 years with bad
prognostic characteristics.
DOI: 10.1007/s00277-005-0012-1
PMID: 16211386 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21059678 | 1. Nucleic Acids Res. 2011 Jan;39(2):e9. doi: 10.1093/nar/gkq1015. Epub 2010 Nov
8.
Accurate quantification of transcriptome from RNA-Seq data by effective length
normalization.
Lee S(1), Seo CH, Lim B, Yang JO, Oh J, Kim M, Lee S, Lee B, Kang C, Lee S.
Author information:
(1)Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience
and Biotechnology (KRIBB), Yuseong-gu, Daejeon, Korea.
We propose a novel, efficient and intuitive approach of estimating mRNA
abundances from the whole transcriptome shotgun sequencing (RNA-Seq) data. Our
method, NEUMA (Normalization by Expected Uniquely Mappable Area), is based on
effective length normalization using uniquely mappable areas of gene and mRNA
isoform models. Using the known transcriptome sequence model such as RefSeq,
NEUMA pre-computes the numbers of all possible gene-wise and isoform-wise
informative reads: the former being sequences mapped to all mRNA isoforms of a
single gene exclusively and the latter uniquely mapped to a single mRNA isoform.
The results are used to estimate the effective length of genes and transcripts,
taking experimental distributions of fragment size into consideration.
Quantitative RT-PCR based on 27 randomly selected genes in two human cell lines
and computer simulation experiments demonstrated superior accuracy of NEUMA over
other recently developed methods. NEUMA covers a large proportion of genes and
mRNA isoforms and offers a measure of consistency ('consistency coefficient')
for each gene between an independently measured gene-wise level and the sum of
the isoform levels. NEUMA is applicable to both paired-end and single-end
RNA-Seq data. We propose that NEUMA could make a standard method in quantifying
gene transcript levels from RNA-Seq data.
DOI: 10.1093/nar/gkq1015
PMCID: PMC3025570
PMID: 21059678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22537040 | 1. BMC Bioinformatics. 2012 Apr 19;13 Suppl 6(Suppl 6):S11. doi:
10.1186/1471-2105-13-S6-S11.
Challenges in estimating percent inclusion of alternatively spliced junctions
from RNA-seq data.
Kakaradov B(1), Xiong HY, Lee LJ, Jojic N, Frey BJ.
Author information:
(1)Department of Electrical and Computer Engineering, University of Toronto, ON,
Canada.
Transcript quantification is a long-standing problem in genomics and estimating
the relative abundance of alternatively-spliced isoforms from the same
transcript is an important special case. Both problems have recently been
illuminated by high-throughput RNA sequencing experiments which are quickly
generating large amounts of data. However, much of the signal present in this
data is corrupted or obscured by biases resulting in non-uniform and
non-proportional representation of sequences from different transcripts. Many
existing analyses attempt to deal with these and other biases with various
task-specific approaches, which makes direct comparison between them difficult.
However, two popular tools for isoform quantification, MISO and Cufflinks, have
adopted a general probabilistic framework to model and mitigate these biases in
a more general fashion. These advances motivate the need to investigate the
effects of RNA-seq biases on the accuracy of different approaches for isoform
quantification. We conduct the investigation by building models of increasing
sophistication to account for noise introduced by the biases and compare their
accuracy to the established approaches. We focus on methods that estimate the
expression of alternatively-spliced isoforms with the percent-spliced-in (PSI)
metric for each exon skipping event. To improve their estimates, many methods
use evidence from RNA-seq reads that align to exon bodies. However, the methods
we propose focus on reads that span only exon-exon junctions. As a result, our
approaches are simpler and less sensitive to exon definitions than existing
methods, which enables us to distinguish their strengths and weaknesses more
easily. We present several probabilistic models of of position-specific read
counts with increasing complexity and compare them to each other and to the
current state-of-the-art methods in isoform quantification, MISO and Cufflinks.
On a validation set with RT-PCR measurements for 26 cassette events, some of our
methods are more accurate and some are significantly more consistent than these
two popular tools. This comparison demonstrates the challenges in estimating the
percent inclusion of alternatively spliced junctions and illuminates the
tradeoffs between different approaches.
DOI: 10.1186/1471-2105-13-S6-S11
PMCID: PMC3330053
PMID: 22537040 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22383165 | 1. Wiley Interdiscip Rev RNA. 2012 Jul-Aug;3(4):455-68. doi: 10.1002/wrna.1109.
Epub 2012 Mar 1.
The 5' → 3' exoribonuclease XRN1/Pacman and its functions in cellular processes
and development.
Jones CI(1), Zabolotskaya MV, Newbury SF.
Author information:
(1)Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton,
UK.
XRN1 is a 5' → 3' processive exoribonuclease that degrades mRNAs after they have
been decapped. It is highly conserved in all eukaryotes, including homologs in
Drosophila melanogaster (Pacman), Caenorhabditis elegans (XRN1), and
Saccharomyces cerevisiae (Xrn1p). As well as being a key enzyme in RNA turnover,
XRN1 is involved in nonsense-mediated mRNA decay and degradation of mRNAs after
they have been targeted by small interfering RNAs or microRNAs. The crystal
structure of XRN1 can explain its processivity and also the selectivity of the
enzyme for 5' monophosphorylated RNA. In eukaryotic cells, XRN1 is often found
in particles known as processing bodies (P bodies) together with other proteins
involved in the 5' → 3' degradation pathway, such as DCP2 and the helicase DHH1
(Me31B). Although XRN1 shows little specificity to particular 5'
monophosphorylated RNAs in vitro, mutations in XRN1 in vivo have specific
phenotypes suggesting that it specifically degrades a subset of RNAs. In
Drosophila, mutations in the gene encoding the XRN1 homolog pacman result in
defects in wound healing, epithelial closure and stem cell renewal in testes. We
propose a model where specific mRNAs are targeted to XRN1 via specific binding
of miRNAs and/or RNA-binding proteins to instability elements within the RNA.
These guide the RNA to the 5' core degradation apparatus for controlled
degradation.
Copyright © 2012 John Wiley & Sons, Ltd.
DOI: 10.1002/wrna.1109
PMID: 22383165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21279724 | 1. Hum Genet. 2011 May;129(5):573-82. doi: 10.1007/s00439-011-0951-7. Epub 2011
Jan 30.
Mutations in Fanconi anemia genes and the risk of esophageal cancer.
Akbari MR(1), Malekzadeh R, Lepage P, Roquis D, Sadjadi AR, Aghcheli K,
Yazdanbod A, Shakeri R, Bashiri J, Sotoudeh M, Pourshams A, Ghadirian P, Narod
SA.
Author information:
(1)Digestive Disease Research Center, Shariati Hospital, Tehran University of
Medical Sciences, North Kargar Street, Tehran, Iran.
The incidence of esophageal squamous cell carcinoma (ESCC) is very high in
northeastern Iran. Previously, we reported a strong familial component of ESCC
among Turkmens, who constitute approximately one-half of the population of this
region. We hypothesized that the genes which cause Fanconi anemia might be
candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi
anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified
three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del),
one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three
patients had a strong family history of ESCC. In addition, four patients (out of
746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none
of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p.
Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was
present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95%
CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous
mutations in several Fanconi anemia-predisposing genes are associated with an
increased risk of ESCC in Iran.
DOI: 10.1007/s00439-011-0951-7
PMID: 21279724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16139842 | 1. J Mol Biol. 2005 Oct 7;352(5):1118-33. doi: 10.1016/j.jmb.2005.08.001.
Design and validation of a neutral protein scaffold for the presentation of
peptide aptamers.
Woodman R(1), Yeh JT, Laurenson S, Ko Ferrigno P.
Author information:
(1)MRC Cancer Cell Unit Hutchison/MRC Research Centre, Hills Road, Cambridge CB2
2 XZ, UK.
Peptide aptamers are peptides constrained and presented by a scaffold protein
that are used to study protein function in cells. They are able to disrupt
protein-protein interactions and to constitute recognition modules that allow
the creation of a molecular toolkit for the intracellular analysis of protein
function. The success of peptide aptamer technology is critically dependent on
the performance of the scaffold. Here, we describe a rational approach to the
design of a new peptide aptamer scaffold. We outline the qualities that an ideal
scaffold would need to possess to be broadly useful for in vitro and in vivo
studies and apply these criteria to the design of a new scaffold, called STM.
Starting from the small, stable intracellular protease inhibitor stefin A, we
have engineered a biologically neutral scaffold that retains the stable
conformation of the parent protein. We show that STM is able to present peptides
that bind to targets of interest, both in the context of known interactors and
in library screens. Molecular tools based on our scaffold are likely to be used
in a wide range of studies of biological pathways, and in the validation of drug
targets.
DOI: 10.1016/j.jmb.2005.08.001
PMID: 16139842 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24138567 | 1. BMC Genomics. 2013 Oct 20;14:720. doi: 10.1186/1471-2164-14-720.
Transcription-factor occupancy at HOT regions quantitatively predicts RNA
polymerase recruitment in five human cell lines.
Foley JW(1), Sidow A.
Author information:
(1)Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford,
California 94305, USA. [email protected].
BACKGROUND: High-occupancy target (HOT) regions are compact genome loci occupied
by many different transcription factors (TFs). HOT regions were initially
defined in invertebrate model organisms, and we here show that they are a
ubiquitous feature of the human gene-regulation landscape.
RESULTS: We identified HOT regions by a comprehensive analysis of ChIP-seq data
from 96 DNA-associated proteins in 5 human cell lines. Most HOT regions
co-localize with RNA polymerase II binding sites, but many are not near the
promoters of annotated genes. At HOT promoters, TF occupancy is strongly
predictive of transcription preinitiation complex recruitment and moderately
predictive of initiating Pol II recruitment, but only weakly predictive of
elongating Pol II and RNA transcript abundance. TF occupancy varies
quantitatively within human HOT regions; we used this variation to discover
novel associations between TFs. The sequence motif associated with any given
TF's direct DNA binding is somewhat predictive of its empirical occupancy, but a
great deal of occupancy occurs at sites without the TF's motif, implying
indirect recruitment by another TF whose motif is present.
CONCLUSIONS: Mammalian HOT regions are regulatory hubs that integrate the
signals from diverse regulatory pathways to quantitatively tune the promoter for
RNA polymerase II recruitment.
DOI: 10.1186/1471-2164-14-720
PMCID: PMC3826616
PMID: 24138567 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14981520 | 1. Nat Genet. 2004 Mar;36(3):271-6. doi: 10.1038/ng1313. Epub 2004 Feb 22.
Heterozygous missense mutations in BSCL2 are associated with distal hereditary
motor neuropathy and Silver syndrome.
Windpassinger C(1), Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R,
Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P,
Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH,
Wagner K.
Author information:
(1)Institute of Medical Biology and Human Genetics, Medical University Graz,
Harrachgasse 21/8, A-8010 Graz, Austria.
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy
(OMIM #182960) is a heterogeneous group of disorders characterized by an almost
exclusive degeneration of motor nerve fibers, predominantly in the distal part
of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary
spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity
of the legs is accompanied by amyotrophy of the hands and occasionally also the
lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly
inherited with incomplete penetrance and a broad variability in clinical
expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed
linkage to the locus SPG17, which was confirmed in 16 additional families with a
phenotype characteristic of dHMN or Silver syndrome. After refining the critical
region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy
(BSCL2) and identified two heterozygous missense mutations resulting in the
amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes
the protein seipin, were previously shown to be associated with autosomal
recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show
that seipin is an integral membrane protein of the endoplasmic reticulum (ER).
The amino acid substitutions N88S and S90L affect glycosylation of seipin and
result in aggregate formation leading to neurodegeneration.
DOI: 10.1038/ng1313
PMID: 14981520 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18289803 | 1. Toxicol Lett. 2008 Mar 15;177(2):130-7. doi: 10.1016/j.toxlet.2008.01.006.
Epub 2008 Jan 19.
Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl
hydrocarbon receptor-dependent and leads to lung inflammation.
Podechard N(1), Lecureur V, Le Ferrec E, Guenon I, Sparfel L, Gilot D, Gordon
JR, Lagente V, Fardel O.
Author information:
(1)UMR-INSERM U620, Team Toxicity of Polycyclic Aromatic Hydrocarbons
(labellisée Ligue contre le Cancer), IFR140, Université de Rennes 1, France.
Benzo(a)pyrene (BP) is an environmental contaminant known to favor airway
inflammation likely through up-regulation of pro-inflammatory cytokines. The
present study was designed to characterize its effects toward interleukin-8
(IL-8), a well-established pulmonary inflammatory cytokine. In primary human
macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion
levels in a dose-dependent manner. Such an up-regulation was likely linked to
aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was
reduced after AhR expression knock-down through RNA interference. Moreover,
electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation
experiments showed BP-triggered binding of AhR to a consensus xenobiotic
responsive element (XRE) found in the human IL-8 promoter. Finally, BP
administration to mice led to over-expression of keratinocyte chemoattractant
(KC), the murine functional homologue of IL-8, in lung. It also triggered the
recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was
however fully abolished in the presence of a chemical antagonist of the KC/IL-8
receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of
KC in BP-induced lung inflammation. Overall, these data highlight an
AhR-dependent regulation of IL-8 in response to BP that likely contributes to
the airway inflammatory effects of this environmental chemical.
DOI: 10.1016/j.toxlet.2008.01.006
PMID: 18289803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17633104 | 1. Rinsho Shinkeigaku. 2007 Jun;47(6):329-35.
[Seipin/BSCL2-related motor neuron disease: Seipinopathy is a novel
conformational disease associated with endoplasmic reticulum stress].
[Article in Japanese]
Ito D(1), Suzuki N.
Author information:
(1)Department of Neurology, School of Medicine, Keio University.
In 2004, heterozygous mutations (N88S, S90L) in the Seipin/BSCL2 gene were
identified in two autosomal dominant motor neuron diseases, distal hereditary
motor neuropathy type V (OMIM #182960) and Silver syndrome (OMIM #270685). The
Seipin/BSCL2 gene was originally identified as a candidate gene for congenital
generalized lipodystrophy type 2 (CGL2) (OMIM #269700). Individuals with
homozygous null mutations in seipin have severe lipoatrophy, insulin resistance,
hypertriglyceridemia, and mental retardation without any abnormality of the
motor neurons. Recent phenotype analyses of the N88S and S90L mutations have
revealed a wide spectrum of Seipin/BSCL2-related motor neuron diseases,
including Silver syndrome, distal hereditary motor neuropathy type V, variants
of Charcot-Marie-Tooth disease type 2, and spastic paraplegia 17; therefore,
these diseases should be termed "seipinopathies". Seipin is a transmembrane
protein that is localized in the endoplasmic reticulum (ER). Interestingly, the
N88S and S90L mutations both disturb the N-glycosylation motif, suggesting that
improper glycosylation of seipin is closely associated with the pathogenesis of
motor neuron diseases. Our recent study demonstrated that seipin is
proteolytically cleaved into N and C-terminal fragments and then
polyubiquitinated. The N88S and S90L mutations enhance ubiquitination and
degradation by UPS, and N88S and S90L mutants appear to be improperly folded,
resulting in their accumulation in the ER. Furthermore, expression of mutant
seipin in cultured cells activates UPR stress and induces ER stress-mediated
apoptosis. Our findings suggest that seipin-related motor neuron diseases,
seipinopathies are novel conformational diseases, and we propose that the
pathological process of these diseases is tightly associated with ER
stress-mediated cell death.
PMID: 17633104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26103569 | 1. Br J Cancer. 2015 Jul 14;113(2):354-63. doi: 10.1038/bjc.2015.231. Epub 2015
Jun 23.
MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the
M-SKIP project.
Tagliabue E(1), Fargnoli MC(2), Gandini S(1), Maisonneuve P(1), Liu F(3), Kayser
M(3), Nijsten T(4), Han J(5), Kumar R(6), Gruis NA(7), Ferrucci L(8), Branicki
W(9), Dwyer T(10), Blizzard L(11), Helsing P(12), Autier P(13), García-Borrón
JC(14), Kanetsky PA(15), Landi MT(16), Little J(17), Newton-Bishop J(18), Sera
F(19), Raimondi S(1); M-SKIP Study Group.
Collaborators: Raimondi S, Autier P, Fargnoli MC, García-Borrón JC, Han J,
Kanetsky PA, Landi MT, Little J, Newton-Bishop J, Sera F, Caini S, Gandini S,
Maisonneuve P, Hofman A, Kayser M, Liu F, Nijsten T, Uitterlinden AG, Kumar R,
Scherer D, Nagore E, Hansson J, Hoiom V, Ghiorzo P, Pastorino L, Gruis NA,
Bavinck NB, Aguilera P, Badenas C, Carrera C, Malvehy J, Mateu MP, Puig S,
Puig-Butille JA, Tell G, Dwyer T, Blizzard L, Cochrane J, Fernandez-de-Misa R,
Branicki W, Debniak T, Morling N, Johansen P, Mayne S, Bale A, Cartmel B,
Ferrucci L, Pfeiffer R, Palmieri G, Biomolecolare C, Ribas G, Stratigos A,
Kypreou K, Sygros A, Bowcock A, Cornelius L, Council M, Motokawa T, Anno S,
Helsing P, Andresen PA, Wong TH, Berwick M, Begg C, Orlow I, Hummer A, Busam K,
Roy P, Canchola R, Clas B, Cotignola J, Monroe Y, Armstrong B, Kricker A,
Litchfield M, Dwyer T, Tucker P, Stephens N, Gallagher R, Switzer T, Marrett L,
Theis B, Chowdhury N, Vanasse L, Purdue M, Northrup D, Zanetti R, Rosso S,
Anton-Culver H, Leighton N, Gildea M, Gruber S, Bonner J, Jeter J, Klotz J,
Wilcox H, Weiss H, Millikan R, Thomas N, Mattingly D, Player J, Tse CK, Rebbeck
T, Kanetsky P, Walker A, Panossian S, Mohrenweiser H, Setlow R.
Author information:
(1)Division of Epidemiology and Biostatistics, European Institute of Oncology,
Via Ripamonti 435, Milan 20141, Italy.
(2)Department of Dermatology, University of L'Aquila, 47100 L'Aquila, Italy.
(3)Department of Forensic Molecular Biology, Erasmus MC University Medical
Center, 3000 DR Rotterdam, The Netherlands.
(4)Department of Dermatology, Erasmus MC University Medical Center, 3000 DR
Rotterdam, The Netherlands.
(5)1] Department of Dermatology, Brigham and Women's Hospital and Harvard
Medical School, Boston, MA 02115, USA [2] Channing Laboratory, Department of
Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
02115, USA [3] Department of Epidemiology, Harvard School of Public Health,
Boston, MA 02115, USA.
(6)Division of Molecular Genetic Epidemiology, German Cancer Research Center,
D-69120 Heidelberg, Germany.
(7)Department of Dermatology, Leiden University Medical Center, 2300 RC Leiden,
The Netherlands.
(8)Department of Chronic Disease Epidemiology, Yale School of Public Health,
Yale Cancer Center, New Haven, CT 06520-8034, USA.
(9)Institute of Forensic Research, 31-033 Krakow, Poland.
(10)Murdoch Childrens Research Institute, Royal Children's Hospital, Victoria
3052, Australia.
(11)Menzies Research Institute Tasmania, University of Tasmania, Hobart, 7001
Australia.
(12)Department of Pathology, Oslo University Hospital, N-0027 Oslo, Norway.
(13)International Prevention Research Institute, Lyon 69006, France.
(14)Department of Biochemistry, Molecular Biology and Immunology, University of
Murcia, 30100 Murcia, Spain.
(15)Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612,
USA.
(16)Division of Cancer Epidemiology and Genetics, National Cancer Institute,
NIH, Bethesda, MD 20892-7236, USA.
(17)School of Epidemiology, Public Health and Preventive Medicine, University of
Ottawa, Ottawa, Canada ON K1N 6N5.
(18)Section of Epidemiology and Biostatistics, Institute of Cancer and
Pathology, University of Leeds, Leeds LS9 7TF, UK.
(19)UCL Institute of Child Health, London WC1N 1EH, UK.
BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation
and is highly polymorphic in populations of European origins. The aims of this
study were to evaluate the association between MC1R variants and the risk of
non-melanoma skin cancer (NMSC), and to investigate whether risk estimates
differed by phenotypic characteristics.
METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the
M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and
phenotypic characteristics. We calculated summary odds ratios (SOR) with
random-effect models, and performed stratified analyses.
RESULTS: Subjects carrying at least one MC1R variant had an increased risk of
NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR
(95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91),
respectively. All of the investigated variants showed positive associations with
NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C,
R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to
2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no
consistent pattern of association between MC1R and NMSC by skin type, but we
consistently observed higher SORs for subjects without red hair.
CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC
development and suggested an effect modification by red hair colour phenotype.
DOI: 10.1038/bjc.2015.231
PMCID: PMC4506395
PMID: 26103569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23612926 | 1. J Interv Card Electrophysiol. 2013 Aug;37(2):131-40. doi:
10.1007/s10840-013-9805-7. Epub 2013 Apr 24.
Novel SCN5A mutations in two families with "Brugada-like" ST elevation in the
inferior leads and conduction disturbances.
Maury P(1), Moreau A, Hidden-Lucet F, Leenhardt A, Fressart V, Berthet M, Denjoy
I, Bennamar N, Rollin A, Cardin C, Guicheney P, Chahine M.
Author information:
(1)Unité de Rythmologie et de Stimulation Cardiaque, Fédération de Cardiologie,
University Hospital Rangueil, 31059, Toulouse, Cedex 09, France.
[email protected]
AIMS: Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST
segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the
cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in
family members with isolated conduction disturbances. However, some patients
show coved ST elevation in the inferior or lateral leads whose association with
SCN5A and familial conduction disturbances are poorly known.
METHODS AND RESULTS: Two novel SCN5A mutations, D1430N and Q1476X, were
identified in two unrelated families comprising patients with Brugada-like ST
elevation located in the inferior leads or isolated conduction disturbances.
Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch
clamp electrophysiological experiments revealed total absence of Na(+) current
resulting from Nav1.5 mutant when compared to WT channels. Treatments known to
restore trafficking defect (incubation at low temperature, with mexiletine or
lidocaine) did not restore Na(+) current supporting that Nav1.5 mutation is not
a defective trafficking mutation. Furthermore, immunocytolabelling indicates the
membrane localisation of both WT and mutant channels confirming what we observed
in our patch clamp experiments. This suggests that the mutation may induce a
complete block of Na(+) permeation. The nonsense mutation Q1476X was leading to
a premature stop codon and was not expressed.
CONCLUSION: Brugada-like ST elevation in the inferior ECG leads or isolated
conduction disturbances were found in two unrelated families and associated with
two novel SCN5A mutations. The missense and nonsense mutations are both
resulting in a complete loss of ventricular Na(+) current explaining the
phenotypes.
DOI: 10.1007/s10840-013-9805-7
PMID: 23612926 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23349747 | 1. PLoS One. 2013;8(1):e53822. doi: 10.1371/journal.pone.0053822. Epub 2013 Jan
18.
Efficient and comprehensive representation of uniqueness for next-generation
sequencing by minimum unique length analyses.
Storvall H(1), Ramsköld D, Sandberg R.
Author information:
(1)Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm,
Sweden.
As next generation sequencing technologies are getting more efficient and less
expensive, RNA-Seq is becoming a widely used technique for transcriptome
studies. Computational analysis of RNA-Seq data often starts with the mapping of
millions of short reads back to the genome or transcriptome, a process in which
some reads are found to map equally well to multiple genomic locations
(multimapping reads). We have developed the Minimum Unique Length Tool (MULTo),
a framework for efficient and comprehensive representation of mappability
information, through identification of the shortest possible length required for
each genomic coordinate to become unique in the genome and transcriptome. Using
the minimum unique length information, we have compared different uniqueness
compensation approaches for transcript expression level quantification and
demonstrate that the best compensation is achieved by discarding multimapping
reads and correctly adjusting gene model lengths. We have also explored
uniqueness within specific regions of the mouse genome and enhancer mapping
experiments. Finally, by making MULTo available to the community we hope to
facilitate the use of uniqueness compensation in RNA-Seq analysis and to
eliminate the need to make additional mappability files.
DOI: 10.1371/journal.pone.0053822
PMCID: PMC3548888
PMID: 23349747 [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/21568860 | 1. Biochemistry (Mosc). 2011 Feb;76(2):260-7. doi: 10.1134/s0006297911020131.
Role of transcription factors in mtDNA biogenesis mediated by thyroid hormones.
Patrushev MV(1), Patrusheva VE.
Author information:
(1)I. Kant Russian State University, Kaliningrad, Russia. [email protected]
Exogenous thyroid hormones are regulators of cellular metabolism that involves,
along with other cell structures, mitochondria. Mechanisms of the influence of
thyroid hormones on the biogenesis of mtDNA are not fully understood due to
their pleiotropic nature. Different ways of regulation of mitochondrial
biogenesis by thyroid hormones are discussed in literature, but thyroid
receptors, localized in both the nucleus and mitochondria, are the main elements
of most pathways. Data on events occurring after receptor activation are rather
contradictory. We investigated the degree of involvement of mitochondrial
transcription factors in the biogenesis of mtDNA induced by triiodothyronine.
The contribution of TFAM, TFB2M, and helicase Twinkle in thyroid-induced mtDNA
biogenesis was assessed. The activation of TFAM and TFB2M expression is shown to
be required for the induction of mtDNA biogenesis. The role of helicase Twinkle,
the expression induction of which is also observed after triiodothyronine
addition, remains unclear. The analysis of factors that activate TFAM and TFB2M
expression showed that NRF-1 is the determinative regulator: deficiency of this
factor leads to complete collapse of mtDNA biogenesis. However, lack of
transcriptional coactivator PGC-1α did not lead to significant reduction in
thyroid-induced biogenesis, whereas literature data point to its key role in the
biogenesis of mitochondria. Thus, in this study the role of key transcription
factors in mtDNA biogenesis induced by triiodothyronine was demonstrated for the
first time in a model system.
DOI: 10.1134/s0006297911020131
PMID: 21568860 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19035757 | 1. J Neurosurg Spine. 2008 Dec;9(6):611-20. doi: 10.3171/SPI.2008.10.08488.
Modulation of the secondary injury process after spinal cord injury in
Bach1-deficient mice by heme oxygenase-1.
Yamada K(1), Tanaka N, Nakanishi K, Kamei N, Ishikawa M, Mizuno T, Igarashi K,
Ochi M.
Author information:
(1)Department of Orthopaedic Surgery, Graduate School of Biomedical Science,
Hiroshima University, Hiroshima, Japan. [email protected]
OBJECT: Oxidative stress contributes to secondary injury after spinal cord
injury (SCI). The expression of heme oxygenase-1 (HO-1), which protects cells
from various insults including oxidative stress, is upregulated in injured
spinal cords. Mice deficient in Bach1 (Bach1-/-), a transcriptional repressor of
the HO-1 and beta-globin genes, express high levels of HO-1 mRNA and protein in
various organs. The authors hypothesized that HO-1 modulates the secondary
injury process after SCI in Bach1(-/-) mice.
METHODS: Male C57BL/6 (wild-type) and homozygous Bach1(-/-) C57BL/6 mice were
subjected to moderate SCI, and differences in hindlimb motor function, and
electrophysiological, molecular biological, and histopathological changes were
assessed for 2 weeks.
RESULTS: Functional recovery was greater, and motor evoked potentials were
significantly larger in Bach1(-/-) mice than in wild-type mice throughout the
observation period. The expression of HO-1 mRNA in the spinal cord was
significantly increased in both mice until 3 days after injury, and it was
significantly higher in Bach1(-/-) mice than in wild-type mice at every
assessment point. Histological examination using Luxol fast blue staining at 1
day after injury showed that the injured areas were smaller in Bach1(-/-) mice
than in wild-type mice. The HO-1 immunoreactivity was not detected in uninjured
spinal cord, but 3 days postinjury the number of HO-1-immunoreactive cells was
obviously higher in the injured area in both mice, particularly in Bach1(-/-)
mice. The HO-1 was primarily induced in microglia/macrophage in both mice.
CONCLUSIONS: These results suggest that HO-1 modulates the secondary injury
process, and high HO-1 expression may preserve spinal cord function in the early
stages after SCI in Bach1(-/-) mice. Treatment that induces HO-1 expression at
these early stages may preserve the functional outcome after SCI.
DOI: 10.3171/SPI.2008.10.08488
PMID: 19035757 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8154209 | 1. Zh Nevrol Psikhiatr Im S S Korsakova. 1993;93(5):17-9.
[Myotonia dystrophica].
[Article in Russian]
Grinshteĭn AB, Goretov AP, Belyĭ EA.
Dystrophic myotonia is a sufficiently rare disease inherited mainly by the
autosomal dominant type. Clinical picture is characterized by the myotonic,
myopathic, and endocrine-autonomic syndrome. A clinical, genetic, and
electromyographic study was carried out to elucidate the problem of this
condition inheritance, its intra- and interfamilial clinical polymorphism, and
effects of environmental factors on its course and outcomes.
PMID: 8154209 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20598714 | 1. J Neurol Sci. 2010 Sep 15;296(1-2):107-9. doi: 10.1016/j.jns.2010.06.015. Epub
2010 Jul 3.
N88S mutation in the BSCL2 gene in a Serbian family with distal hereditary motor
neuropathy type V or Silver syndrome.
Rakocević-Stojanović V(1), Milić-Rasić V, Perić S, Baets J, Timmerman V, Dierick
I, Pavlović S, De Jonghe P.
Author information:
(1)Institute of Neurology, Clinical Center of Serbia, School of Medicine,
University of Belgrade, 6, Dr Subotica Street, 11000 Belgrade, Serbia.
[email protected]
BACKGROUND: Distal hereditary motor neuropathy type V (dHMN-V) and Silver
syndrome are rare phenotypically overlapping diseases which can be caused by
mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or
Seipin.
AIM: To report the first Serbian family with a BSCL2 mutation showing variable
expression within the family.
PATIENTS AND METHODS: A 55-year-old woman presented with weakness of both hands
at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in
her legs. Physical examination revealed atrophy and weakness of small hand
muscles and mild atrophy and weakness of the lower limbs. There was generalized
hyperreflexia with the exception of ankle reflexes which were diminished. Her
25year-old son had only stiffness of both legs at the age of 22. Physical
examination revealed only generalized hyporeflexia. The third affected member in
this family was her 55year-old cousin who showed a more prominent involvement of
leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal
tract features.
RESULTS: In all three patients sensory nerve conduction velocities (NCV) were
normal in all extremities. Compound muscle action potential (CMAP) amplitudes
were markedly reduced in all patients. Concentric needle EMG showed evidence of
chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and
a heterozygous N88S missense mutation in BSCL2 gene was detected in all three
patients.
CONCLUSION: This report is further confirmation of phenotypic heterogenity due
to the N88S mutation of BSCL2 gene in the same family.
2010. Published by Elsevier B.V.
DOI: 10.1016/j.jns.2010.06.015
PMID: 20598714 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11285265 | 1. J Biol Chem. 2001 Jun 22;276(25):22100-6. doi: 10.1074/jbc.M101469200. Epub
2001 Apr 2.
alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative
voltages.
Koschak A(1), Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J.
Author information:
(1)Institut für Biochemische Pharmakologie, Peter-Mayr-Strasse 1, A-6020
Innsbruck, Austria.
In cochlea inner hair cells (IHCs), L-type Ca(2+) channels (LTCCs) formed by
alpha1D subunits (D-LTCCs) possess biophysical and pharmacological properties
distinct from those of alpha1C containing C-LTCCs. We investigated to which
extent these differences are determined by alpha1D itself by analyzing the
biophysical and pharmacological properties of cloned human alpha1D splice
variants in tsA-201 cells. Variant alpha1D(8A,) containing exon 8A sequence in
repeat I, yielded alpha1D protein and L-type currents, whereas no intact protein
and currents were observed after expression with exon 8B. In whole cell
patch-clamp recordings (charge carrier 15-20 mm Ba(2+)), alpha1D(8A) - mediated
currents activated at more negative voltages (activation threshold, -45.7 versus
-31.5 mV, p < 0.05) and more rapidly (tau(act) for maximal inward currents 0.8
versus 2.3 ms; p < 0.05) than currents mediated by rabbit alpha1C. Inactivation
during depolarizing pulses was slower than for alpha1C (current inactivation
after 5-s depolarizations by 90 versus 99%, p < 0.05) but faster than for LTCCs
in IHCs. The sensitivity for the dihydropyridine (DHP) L-type channel blocker
isradipine was 8.5-fold lower than for alpha1C. Radioligand binding experiments
revealed that this was not due to a lower affinity for the DHP binding pocket,
suggesting that differences in the voltage-dependence of DHP block account for
decreased sensitivity of D-LTCCs. Our experiments show that alpha1D(8A) subunits
can form slowly inactivating LTCCs activating at more negative voltages than
alpha1C. These properties should allow D-LTCCs to control physiological
processes, such as diastolic depolarization in sinoatrial node cells,
neurotransmitter release in IHCs and neuronal excitability.
DOI: 10.1074/jbc.M101469200
PMID: 11285265 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19568611 | 1. Yonsei Med J. 2009 Jun 30;50(3):448-51. doi: 10.3349/ymj.2009.50.3.448. Epub
2009 Jun 24.
A case of catecholaminergic polymorphic ventricular tachycardia.
Lee SY(1), Kim JB, Im E, Yang WI, Joung B, Lee MH, Kim SS.
Author information:
(1)Division of Cardiology, Yonsei Cardiovascular Center and Cardiovascular
Research Institute, Yonsei University College of Medicine, 250 Seongsan-ro,
Seodaemun-gu,Seoul, Korea.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial
cardiac arrhythmia that is related to RYR2 or CASQ2 gene mutation. It occurs in
patients with structurally normal heart and causes exercise-emotion-triggered
syncope and sudden cardiac death. We experienced a case of CPVT in an 11
year-old female patient who was admitted for sudden cardiovascular collapse. The
initial electrocardiogram (ECG) on emergency department revealed ventricular
fibrillation. After multiple defibrillations, sinus rhythm was restored.
However, recurrent ventricular fibrillation occurred during insertion of
nasogastric tube without sedation in coronary care unit. On ECG monitoring,
bidirectional ventricular tachycardia occurred with sinus tachycardia and then
degenerated into ventricular fibrillation. To our knowledge, there has been no
previous case report of CPVT triggered by sinus tachycardia in Korea. Therefore,
we report the case as well as a review of the literature.
DOI: 10.3349/ymj.2009.50.3.448
PMCID: PMC2703772
PMID: 19568611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21549050 | 1. J Food Prot. 2011 May;74(5):789-95. doi: 10.4315/0362-028X.JFP-10-435.
Liquid chromatography-tandem mass spectrometry determination of the toxicity and
identification of fish species in a suspected tetrodotoxin fish poisoning.
Wu YJ(1), Cheng YJ, Jen HC, Pan CH, Lin TC, Lin SJ, Hwang DF.
Author information:
(1)Department of Food Science, National Taiwan Ocean University, Keelung,
Taiwan.
Suspected tetrodotoxin (TTX) poisoning was associated with eating unknown fish
in April 2009 in Taiwan. After ingestion of the fish, symptoms of the victim
included perioral paresthesia, nausea, vomiting, ataxia, weakness of all limbs,
respiration failure, and death within several hours. The toxicity in the
remaining fish was determined, with the mice exhibiting symptoms of neurotoxin
poisoning. The implicated fish and deceased victim tissues were analyzed for TTX
by liquid chromatography-tandem mass spectrometry. The urine, bile,
cerebrospinal fluid (spinal cord), pleural effusion, and pericardial effusion of
the victim contained TTX. In addition, the partial cytochrome b gene of the
implicated fish was determined by PCR. The DNA sequence in the partial 465-bp
cytochrome b gene identified the implicated fish as Chelonodon patoca (puffer
fish). These results indicate that people should avoid eating unknown fish
species from fish markets where harvested fish may include toxic species.
DOI: 10.4315/0362-028X.JFP-10-435
PMID: 21549050 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15913575 | 1. Cardiovasc Res. 2005 Aug 15;67(3):379-87. doi:
10.1016/j.cardiores.2005.04.027.
Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic
insights.
Kontula K(1), Laitinen PJ, Lehtonen A, Toivonen L, Viitasalo M, Swan H.
Author information:
(1)Department of Medicine, University of Helsinki, 00290 Helsinki, Finland.
[email protected]
Cardiac excitation-contraction coupling occurs by a calcium ion-mediated
mechanism in which the signal of action potential is converted into Ca2+ influx
into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is
followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the
sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2).
RyR2 channels form large complexes with additional regulatory proteins,
including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into
the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+
release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic
polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and
highly malignant, inherited disorder characterized by effort-induced ventricular
arrhythmias in the absence of structural alterations of the heart. At least some
cases of sudden, unexplained death in young individuals may be ascribed to CPVT.
Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the
CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps
of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate
"leakiness" of RyR2 channels is thought to play a role; the underlying
mechanisms may involve an increase in the basal activity of the RyR2 channel,
alterations in its phosphorylation status, a defective interaction of RyR2 with
other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal
activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have
proven to be of value in prevention of arrhythmias in CPVT patients, but
occasional treatment failures call for alternative measures. There is great
interest at present for the development of novel antiarrhythmic drugs for CPVT,
as the same approaches may be applied for treatment of more common forms of
life-threatening arrhythmias, such as those arising during ischemia and heart
failure.
DOI: 10.1016/j.cardiores.2005.04.027
PMID: 15913575 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20803659 | 1. Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):365-76. doi:
10.1002/ajmg.c.30273.
Prader-Willi syndrome and Angelman syndrome.
Buiting K(1).
Author information:
(1)Institute of Human Genetics at the University Hospital Essen, Essen, Germany.
[email protected]
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct
neurogenetic disorders in which imprinted genes on the proximal long arm of
chromosome 15 are affected. Although the SNORD116 gene cluster has become a
prime candidate for PWS, it cannot be excluded that other paternally expressed
genes in the chromosomal region 15q11q13 contribute to the full phenotype. AS is
caused by a deficiency of the UBE3A gene, which in the brain is expressed from
the maternal allele only. The most frequent genetic lesions in both disorders
are a de novo deletion of the chromosomal region 15q11q13, uniparental disomy
15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene.
Microdeletions in a small number of patients with PWS and AS have led to the
identification of the chromosome 15 imprinting center (IC). The IC consists of
two critical elements, which act in cis to regulate imprinting in the whole
chromosome 15q11q13 imprinted domain.
DOI: 10.1002/ajmg.c.30273
PMID: 20803659 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18790747 | 1. Mol Cancer Ther. 2008 Sep;7(9):2649-61. doi: 10.1158/1535-7163.MCT-08-0148.
Interleukin-8 signaling attenuates TRAIL- and chemotherapy-induced apoptosis
through transcriptional regulation of c-FLIP in prostate cancer cells.
Wilson C(1), Wilson T, Johnston PG, Longley DB, Waugh DJ.
Author information:
(1)Centre for Cancer Research and Cell Biology, Queens University Belfast, 97
Lisburn Road, Belfast, Northern Ireland BT9 7BL, United Kingdom.
Chemotherapy-induced interleukin-8 (IL-8) signaling reduces the sensitivity of
prostate cancer cells to undergo apoptosis. In this study, we investigated how
endogenous and drug-induced IL-8 signaling altered the extrinsic apoptosis
pathway by determining the sensitivity of LNCaP and PC3 cells to administration
of the death receptor agonist tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL). TRAIL induced concentration-dependent decreases in LNCaP and PC3
cell viability, coincident with increased levels of apoptosis and the
potentiation of IL-8 secretion. Administration of recombinant human IL-8 was
shown to increase the mRNA transcript levels and expression of c-FLIP(L) and
c-FLIP(S), two isoforms of the endogenous caspase-8 inhibitor. Pretreatment with
the CXCR2 antagonist AZ10397767 significantly attenuated IL-8-induced c-FLIP
mRNA up-regulation whereas inhibition of androgen receptor- and/or nuclear
factor-kappaB-mediated transcription attenuated IL-8-induced c-FLIP expression
in LNCaP and PC3 cells, respectively. Inhibition of c-FLIP expression was shown
to induce spontaneous apoptosis in both cell lines and to sensitize these
prostate cancer cells to treatment with TRAIL, oxaliplatin, and docetaxel.
Coadministration of AZ10397767 also increased the sensitivity of PC3 cells to
the apoptosis-inducing effects of recombinant TRAIL, most likely due to the
ability of this antagonist to block TRAIL- and IL-8-induced up-regulation of
c-FLIP in these cells. We conclude that endogenous and TRAIL-induced IL-8
signaling can modulate the extrinsic apoptosis pathway in prostate cancer cells
through direct transcriptional regulation of c-FLIP. Therefore, targeted
inhibition of IL-8 signaling or c-FLIP expression in prostate cancer may be an
attractive therapeutic strategy to sensitize this stage of disease to
chemotherapy.
DOI: 10.1158/1535-7163.MCT-08-0148
PMID: 18790747 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23329413 | 1. Bioinformatics. 2013 Mar 1;29(5):614-21. doi: 10.1093/bioinformatics/btt016.
Epub 2013 Jan 17.
Grape RNA-Seq analysis pipeline environment.
Knowles DG(1), Röder M, Merkel A, Guigó R.
Author information:
(1)Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG) and
Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain.
[email protected]
MOTIVATION: The avalanche of data arriving since the development of NGS
technologies have prompted the need for developing fast, accurate and easily
automated bioinformatic tools capable of dealing with massive datasets. Among
the most productive applications of NGS technologies is the sequencing of
cellular RNA, known as RNA-Seq. Although RNA-Seq provides similar or superior
dynamic range than microarrays at similar or lower cost, the lack of standard
and user-friendly pipelines is a bottleneck preventing RNA-Seq from becoming the
standard for transcriptome analysis.
RESULTS: In this work we present a pipeline for processing and analyzing RNA-Seq
data, that we have named Grape (Grape RNA-Seq Analysis Pipeline Environment).
Grape supports raw sequencing reads produced by a variety of technologies,
either in FASTA or FASTQ format, or as prealigned reads in SAM/BAM format. A
minimal Grape configuration consists of the file location of the raw sequencing
reads, the genome of the species and the corresponding gene and transcript
annotation. Grape first runs a set of quality control steps, and then aligns the
reads to the genome, a step that is omitted for prealigned read formats. Grape
next estimates gene and transcript expression levels, calculates exon inclusion
levels and identifies novel transcripts. Grape can be run on a single computer
or in parallel on a computer cluster. It is distributed with specific mapping
and quantification tools, but given its modular design, any tool supporting
popular data interchange formats can be integrated.
AVAILABILITY: Grape can be obtained from the Bioinformatics and Genomics website
at: http://big.crg.cat/services/grape.
DOI: 10.1093/bioinformatics/btt016
PMCID: PMC3582270
PMID: 23329413 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23442556 | 1. BMC Cancer. 2013 Feb 26;13:89. doi: 10.1186/1471-2407-13-89.
A randomised controlled trial of a mindfulness intervention for men with
advanced prostate cancer.
Chambers SK(1), Smith DP, Berry M, Lepore SJ, Foley E, Clutton S, McDowall R,
Occhipinti S, Frydenberg M, Gardiner RA.
Author information:
(1)Griffith Health Institute, Griffith University, 4222, Gold Coast, QLD,
Australia. [email protected]
BACKGROUND: Prostate cancer is the most common male cancer in developed
countries, and in Australia approximately one-fifth of men with prostate cancer
have advanced disease. By comparison to men with localised prostate cancer, men
with advanced disease report higher levels of psychological distress; poorer
quality of life; and have an increased risk of suicide. To date no psychological
intervention research specifically targeting men with advanced prostate cancer
has been reported. In this paper we present the protocol of a current randomised
controlled trial to assess the effectiveness of a professionally-led
mindfulness-based cognitive therapy (MBCT) group intervention to improve
psychological well-being in men with advanced prostate cancer.
METHODS/DESIGN: Ninety-five men per condition (190 men in total) will be
recruited through clinicians in the Australian and New Zealand Urogenital and
Prostate Cancer Trials Group and in major treatment centres in Queensland, New
South Wales, Victoria and Western Australia. Patients are randomised to: (1)
tele-based MBCT intervention or (2) patient education. A series of previously
validated and reliable self-report measures will be administered to men at four
time points: baseline/recruitment, and at 3, 6, and 9 months after recruitment
and intervention commencement. Engagement with the principles of mindfulness and
adherence to practice will be included as potential mediators of intervention
effect. Primary outcomes are anxiety, depression and cancer-specific distress.
Secondary outcomes are health-related quality of life (QoL) and benefit finding.
Disease variables (e.g. cancer grade, stage) will be assessed through medical
records.
DISCUSSION: This study will address a critical but as yet unanswered research
question: to identify an effective way to reduce psychological distress; and
improve the quality of life for men with advanced prostate cancer.
TRIAL REGISTRATION: http://ACTRN12612000306819.
DOI: 10.1186/1471-2407-13-89
PMCID: PMC3598536
PMID: 23442556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9398449 | 1. Exp Neurol. 1997 Nov;148(1):45-50. doi: 10.1006/exnr.1997.6611.
Effects of isradipine, an L-type calcium channel blocker on permanent and
transient focal cerebral ischemia in spontaneously hypertensive rats.
Campbell CA(1), Mackay KB, Patel S, King PD, Stretton JL, Hadingham SJ, Hamilton
TC.
Author information:
(1)SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.
Permanent or transient focal cerebral ischemia was induced in spontaneously
hypertensive rats (SHR) using the intraluminal filament method. Successful
occlusion of the middle cerebral artery (MCA) was achieved using 4/O filaments
(terminal diameter 0.20-0.25 mm) coated with poly-L-lysine. The L-type calcium
channel blocker isradipine (2.5 mg/kg) administered subcutaneously 30 min
following permanent MCA occlusion significantly reduced the volume of ischemic
brain damage in the cerebral hemisphere (25%; P = 0.0001), cerebral cortex (18%;
P = 0.0034), and caudate nucleus (33%; P = 0.0002) when assessed at 24 h
post-MCA occlusion. Isradipine did not affect the functional deficit (measured
using a subjective neurological scoring system) induced by MCA occlusion. In SHR
undergoing transient (2 h) MCA occlusion isradipine administered 30 min post-MCA
occlusion produced a significant reduction (47%; P = 0.001) in hemispheric
infarct volume, whereas isradipine administered at the onset of reperfusion did
not confer any significant neuroprotection. No change in functional deficit was
seen with isradipine with either dosing paradigm at 24 h post-MCA occlusion.
These results demonstrate that the intraluminal filament method of MCA occlusion
can be used in the SHR strain and also substantiates the neuroprotective
efficacy of isradipine in SHR models of permanent and transient focal cerebral
ischemia.
DOI: 10.1006/exnr.1997.6611
PMID: 9398449 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19199459 | 1. J Neurosurg. 2009 May;110(5):968-74. doi: 10.3171/2008.10.JNS08901.
Simvastatin for the prevention of symptomatic cerebral vasospasm following
aneurysmal subarachnoid hemorrhage: a single-institution prospective cohort
study.
McGirt MJ(1), Garces Ambrossi GL, Huang J, Tamargo RJ.
Author information:
(1)Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore,
Maryland, USA.
OBJECT: Vasospasm is the major cause of disability and death after aneurysmal
subarachnoid hemorrhage (aSAH). Although the results of 2 randomized clinical
trials demonstrated that statin decreases the incidence of symptomatic cerebral
vasospasm after aSAH, retrospective studies have failed to confirm this. The
authors conducted a prospective observational study to determine whether a
standardized regimen of simvastatin would reduce the incidence of cerebral
vasospasm and improve neurological outcomes in patients with aSAH.
METHODS: Since 1991, all patients with aSAH admitted to the authors' institution
have been prospectively followed up with standardized outcomes recording.
Starting in September 2005, all patients admitted with aSAH were given enteral
simvastatin (80 mg/day for 14 days) in addition to the standard care. The
incidence of symptomatic cerebral vasospasm, length of hospitalization,
in-hospital mortality rate, and discharge Glasgow Outcome Scale scores in these
170 patients were compared to data obtained in 170 consecutive patients who
underwent treatment in our unit prior to the introduction of statin therapy.
RESULTS: The 5-year study period included 340 consecutively treated patients
(170 who received statins and 170 who did not). Patients who received
simvastatin therapy were more frequently male (29 vs 20%) and had a smaller
median aneurysm diameter (6 vs 7 mm). Baseline characteristics were otherwise
similar between the cohorts. There were no differences in the incidence of
symptomatic vasospasm (25.3 vs 30.5%; p = 0.277), in-hospital mortality rate (18
vs 15%; p = 0.468), length of hospitalization (21 +/- 15 vs 19 +/- 12 days; p =
0.281), or poor outcome at discharge (Glasgow Outcome Scale Scores 1-2: 21.7 vs
18.2%; p = 0.416) between the simvastatin and nonstatin cohorts. There were no
statin-related complications.
CONCLUSIONS: The uniform introduction of simvastatin did not reduce the
incidence of symptomatic cerebral vasospasm, death, or poor outcome in patients
with aSAH. Simvastatin was well tolerated, but its benefit may be less than has
been previously reported.
DOI: 10.3171/2008.10.JNS08901
PMID: 19199459 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8800628 | 1. Drug Saf. 1996 May;14(5):329-42. doi: 10.2165/00002018-199614050-00005.
Bodyweight change as an adverse effect of drug treatment. Mechanisms and
management.
Pijl H(1), Meinders AE.
Author information:
(1)Department of General Internal Medicine, Leiden University Hospital, The
Netherlands.
A number of drugs are capable of changing bodyweight as an adverse effect of
their therapeutic action. Bodyweight gain is more of a problem than bodyweight
loss. As bodyweight gain during drug treatment for any kind of disease may be
the reflection of improvement of the disease itself, we will try to separate
these effects from those due to drug-induced alterations of the mechanisms
regulating bodyweight. Bodyweight gain may jeopardise patient compliance to the
prescribed regimen and it may pose health risks. The body mass index (BMI) is
determined by dividing bodyweight in kilograms by height in metres squared. A
BMI of > or = 27 kg/m2 warrants therapeutic action; nutritional counselling and
programmed physical exercise can be used as a basis. In general, if basic
therapeutic measures are unsuccessful at controlling bodyweight gain then a
change of drug might help. Finally, an anoretic drug may serve to support
dietary measures. However, safety and efficacy has been demonstrated for only a
few anorectic drugs when used as an adjunct to caloric restriction in the
treatment of drug-induced obesity. Bodyweight is determined by complex
mechanisms regulating energy balance. A number of neurotransmitter systems
acting in several hypothalamic nuclei are pivotal to the regulation of body fat
stores. Most drugs that are capable of changing bodyweight interfere with these
neurotransmitter systems. The increment is dependent on the type and dose of the
drug concerned. Some antidepressant drugs induce bodyweight gain, which may
amount to 20 kg over several months of treatment. Monoamine oxidase inhibitors
appear to cause less bodyweight change than tricyclic antidepressants. Selective
serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors cause bodyweight loss
instead of bodyweight gain. Lithium may cause large increases in bodyweight.
Generally speaking, the bodyweight change induced by antipsychotics is more
often of clinical significance than the bodyweight change associated with the
use of antidepressants. Again, the changes of bodyweight are dependent upon the
type and dose of the antipsychotic drug involved. Although almost all
antipsychotics induce bodyweight gain, molindone and loxapine appear to induce
bodyweight loss. Anticonvulsants, especially valproic acid (sodium valproate)
and carbamazepine, induce bodyweight gain in a considerable percentage of
patients. Treatment with corticosteroids is associated with dose-dependent
bodyweight gain in many patients. Corticosteroid-induced obesity aggravates
other corticosteroid-associated health risks. Insulin therapy in diabetic
patients usually increases bodyweight. Finally, sulphonurea derivatives,
antineoplastic agents used for the treatment of breast cancer and several drugs
used in migraine prophylaxis may cause bodyweight gain as well.
DOI: 10.2165/00002018-199614050-00005
PMID: 8800628 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22298808 | 1. Circ Res. 2012 Mar 2;110(5):663-8. doi: 10.1161/CIRCRESAHA.111.263939. Epub
2012 Jan 31.
Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural
abnormalities in adult calsequestrin-null mice with inherited arrhythmias.
Denegri M(1), Avelino-Cruz JE, Boncompagni S, De Simone SA, Auricchio A, Villani
L, Volpe P, Protasi F, Napolitano C, Priori SG.
Author information:
(1)Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
RATIONALE: Catecholaminergic polymorphic ventricular tachycardia is an inherited
disease that predisposes to cardiac arrest and sudden death. The disease is
associated with mutations in the genes encoding for the cardiac ryanodine
receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a
major loss of CASQ2 monomers, possibly because of enhanced degradation of the
mutant protein. The decrease of CASQ2 is associated with a reduction in the
levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2
and RyR2, a macromolecular complex devoted to control of calcium release from
the sarcoplasmic reticulum.
OBJECTIVE: We intended to evaluate whether viral gene transfer of wild-type
CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2.
METHODS AND RESULTS: We used an adeno-associated serotype 9 viral vector to
express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after
intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed
normalization of the levels of calsequestrin, triadin, and junctin, rescue of
electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation,
and lack of life-threatening arrhythmias.
CONCLUSIONS: We have proven the concept that induction of CASQ2 expression in
knockout mice reverts the molecular, structural, and electric abnormalities and
prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic
polymorphic ventricular tachycardia mice. These data support the view that
development of CASQ2 viral gene transfer could have clinical application.
DOI: 10.1161/CIRCRESAHA.111.263939
PMID: 22298808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25011997 | 1. Virchows Arch. 2014 Sep;465(3):359-64. doi: 10.1007/s00428-014-1626-2. Epub
2014 Jul 11.
Increased lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related
thyroid disease).
Cameselle-Teijeiro J(1), Ladra MJ, Abdulkader I, Eloy C, Soares P, Barreiro F,
Sobrinho-Simões M, Beiras-Iglesias A.
Author information:
(1)Department of Pathology, Clinical University Hospital, Galician Health
Service (SERGAS), Health Research Institute of Santiago de Compostela (IDIS),
Santiago de Compostela, Spain, [email protected].
The present study describes in depth a case of Riedel thyroiditis (RT) to
clarify its pathogenesis and its putative inclusion in the spectrum of
IgG4-related disease. We report the clinicopathological, immunohistochemical,
and ultrastructural features of a case of RT in a 39-year-old white Spanish
woman, admitted with a hard goiter and cold nodule in the left thyroid lobe.
This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies
performed in our hospital. More than 80 % of the left thyroid lobe was effaced
by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1
high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension
into the surrounding tissues and occlusive phlebitis. Immunostaining for
podoplanin (D2-40) detected signs of increased lymphangiogenesis in the
fibroinflammatory areas that were confirmed by electron microscopy. A strong,
diffuse stain for podoplanin and transforming growth factor ß1 was also detected
in the same areas. The increased number of lymphatic vessels in RT is reported
for the first time. Our findings support the inclusion of RT within the spectrum
of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and
physiopathology of IgG4-RTD still remain elusive, the results obtained in the
present case suggest the participation of lymphatic vessels in the pathogenesis
of RT.
DOI: 10.1007/s00428-014-1626-2
PMID: 25011997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10796464 | 1. Cochrane Database Syst Rev. 2000;(2):CD002083. doi: 10.1002/14651858.CD002083.
Molindone for schizophrenia and severe mental illness.
Bagnall A(1), Fenton M, Lewis R, Leitner ML, Kleijnen J.
Author information:
(1)NHS Centre for Reviews and Dissemination, University of York, York, North
Yorkshire, UK, YO10 5DD. [email protected]
Update in
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002083. doi:
10.1002/14651858.CD002083.pub2.
BACKGROUND: Typical antipsychotic drugs are widely used as the first line
treatment for people with schizophrenia. However, the atypical class of
antipsychotic drugs is making important inroads into this approach. 'Atypical'
is a term widely used to describe some antipsychotics which have a low
propensity to produce movement disorders, sedation and raised serum prolactin.
There is some suggestion that the different adverse effect profiles of the
atypical antipsychotic group make them more acceptable to people with
schizophrenia. Molindone has a similar profile to quetiapine (a novel atypical
antipsychotic), with very low binding to all receptors. Some authors have
suggested that molindone is safer than other 'typical' antipsychotics in that
extrapyramidal adverse effects are not usually seen at clinically effective
antipsychotic doses and that it should therefore be classed as an atypical
antipsychotic.
OBJECTIVES: To determine the effects of molindone compared with placebo, typical
and other atypical antipsychotic drugs for schizophrenia and related psychoses.
SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The
Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's
Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE
(1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999)
were undertaken. In addition, pharmaceutical databases on the Dialog Corporation
Datastar and Dialog services were searched. References of all identified studies
were searched for further trials. The manufacturer of molindone and authors of
trials were contacted.
SELECTION CRITERIA: All randomised controlled trials that compared molindone to
other treatments for schizophrenia and schizophrenia-like psychoses were
included by independent assessment.
DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were
independently inspected by reviewers, papers ordered, re-inspected and quality
assessed. Data were independently extracted. Data were excluded if loss to
follow up was greater than 50%. For homogeneous dichotomous data the risk ratio
(RR), 95% confidence interval (CI) and, where appropriate, the number needed to
treat (NNT) were calculated on an intention-to-treat basis. For continuous data,
weighted mean differences (WMD) were calculated. All data were inspected for
heterogeneity.
MAIN RESULTS: Thirteen studies were included in the review. Data for this
compound range from very short (10 day) studies of the intramuscular preparation
to trials lasting over three months. For measures of global state available data
do not justify any conclusions on the comparative efficacy of molindone and
placebo. When compared to other typical antipsychotics no difference in
effectiveness was evidenced (doctors' RR 1.13, CI 0.69 to 1.86; nurses' RR 1.23,
CI 0.82 to 1.86). It is no more or less likely than typical drugs to cause
movement disorders, but causes significantly more weight loss (RR 2.78, CI 1.10
to 6.99).
REVIEWER'S CONCLUSIONS: The strength of the evidence relating to this compound
is limited, owing to small sample size, poor study design, limited outcomes and
incomplete reporting. Molindone may be an effective antipsychotic; however, its
adverse effect profile does not differ significantly from that of typical
antipsychotics, apart from the event of weight loss. At present there is no
evidence to suggest that it may have an atypical profile.
DOI: 10.1002/14651858.CD002083
PMID: 10796464 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11283860 | 1. Hepatology. 2001 Apr;33(4):956-62. doi: 10.1053/jhep.2001.23500.
In vitro and in vivo activation of rat hepatic stellate cells results in de novo
expression of L-type voltage-operated calcium channels.
Bataller R(1), Gasull X, Ginès P, Hellemans K, Görbig MN, Nicolás JM, Sancho-Bru
P, De Las Heras D, Gual A, Geerts A, Arroyo V, Rodés J.
Author information:
(1)Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona School of
Medicine, Catalunya, Spain.
Comment in
Hepatology. 2001 Apr;33(4):1007-8. doi: 10.1053/jhep.2001.23901.
Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate
into myofibroblast-like cells, which develop contractile properties and
contribute to increased resistance to blood flow. We investigated whether this
phenotypic activation includes changes in the expression of L-type
voltage-operated Ca2+ channels (VOCC), which mediate Ca2+ influx and regulate
cell contraction in vascular cell types. Rat HSCs were studied in the quiescent
phenotype and after their activation in vitro (cultured on plastic for 14 days)
and in vivo (isolated from rats with CCl(4)-induced cirrhosis). Patch-clamp
studies showed Ca2+ currents through L-type VOCC in HSCs activated both in vitro
and in vivo, whereas no currents were detected in quiescent HSCs. Moreover,
binding studies with (3)H-isradipine, a specific L-type VOCC antagonist, showed
a large number of binding sites in activated HSCs, while no specific binding was
found in quiescent HSCs. Finally, messenger RNA (mRNA) encoding L-type VOCC was
not detected in quiescent HSCs as assessed by reverse transcription-polymerase
chain reaction (RT-PCR) and Northern blot analysis, whereas it was present in
activated HSCs. Stimulation of L-type VOCC with KCl resulted in a marked
increase in [Ca2+](i) followed by cell contraction in HSCs activated both in
vitro and in vivo, whereas no effects were observed in quiescent HSCs. We
conclude that the activation of HSCs is associated with up-regulation of L-type
VOCC that mediate Ca2+ influx and cell contraction. These results may be
relevant to the pathogenesis of portal hypertension.
DOI: 10.1053/jhep.2001.23500
PMID: 11283860 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2238088 | 1. Trends Genet. 1990 Sep;6(9):300-4. doi: 10.1016/0168-9525(90)90236-y.
Transcriptional enhancers can act in trans.
Müller HP(1), Schaffner W.
Author information:
(1)Institut für Molekularbiologie II, Universität Zürich, Switzerland.
Enhancers have been defined operationally as cis-regulatory sequences that can
stimulate transcription of RNA polymerase-II-transcribed genes over large
distances and even when located downstream of the gene. Recently, it has become
evident that enhancers can also stimulate transcription in trans if they are
brought into close proximity to the promoter/gene. These reports provide clues
to the mechanism of remote enhancer action. In addition, the findings, together
with genetic studies in Drosophila, strongly suggest that enhancer action in
trans could underlie phenomena such as 'transvection', where one chromosome
affects gene expression in the paired homolog.
DOI: 10.1016/0168-9525(90)90236-y
PMID: 2238088 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24631294 | 1. Exp Cell Res. 2014 May 1;323(2):314-25. doi: 10.1016/j.yexcr.2014.02.027. Epub
2014 Mar 11.
Roles of mitochondrial fragmentation and reactive oxygen species in
mitochondrial dysfunction and myocardial insulin resistance.
Watanabe T(1), Saotome M(2), Nobuhara M(1), Sakamoto A(1), Urushida T(1), Katoh
H(1), Satoh H(1), Funaki M(3), Hayashi H(1).
Author information:
(1)Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1
Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
(2)Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1
Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Electronic address:
[email protected].
(3)Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1
Kuramoto-cho, Tokushima 770-8503, Japan.
PURPOSE: Evidence suggests an association between aberrant mitochondrial
dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by
insulin resistance plays a crucial role in heart disease, we investigated the
role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the
pathogenesis of myocardial insulin resistance.
METHODS AND RESULTS: DRP1-expressing H9c2 myocytes, which had fragmented
mitochondria with mitochondrial membrane potential (ΔΨm) depolarization,
exhibited attenuated insulin signaling and 2-deoxy-d-glucose (2-DG) uptake,
indicating insulin resistance. Treatment of the DRP1-expressing myocytes with
Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly
improved insulin resistance and mitochondrial dysfunction. When myocytes were
exposed to hydrogen peroxide (H2O2), they increased DRP1 expression and
mitochondrial fragmentation, resulting in ΔΨm depolarization and insulin
resistance. When DRP1 was suppressed by siRNA, H2O2-induced mitochondrial
dysfunction and insulin resistance were restored. Our results suggest that a
mutual enhancement between DRP1 and reactive oxygen species could induce
mitochondrial dysfunction and myocardial insulin resistance. In
palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP
restored the ΔΨm depolarization and impaired 2-DG uptake, however they improved
insulin signaling.
CONCLUSIONS: A mutual enhancement between DRP1 and ROS could promote
mitochondrial dysfunction and inhibition of insulin signal transduction.
However, other mechanisms, including lipid metabolite-induced mitochondrial
dysfunction, may be involved in palmitate-induced insulin resistance.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.yexcr.2014.02.027
PMID: 24631294 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21880592 | 1. Nucleic Acids Res. 2011 Dec;39(22):9720-30. doi: 10.1093/nar/gkr684. Epub 2011
Aug 31.
Direct cloning of double-stranded RNAs from RNase protection analysis reveals
processing patterns of C/D box snoRNAs and provides evidence for widespread
antisense transcript expression.
Shen M(1), Eyras E, Wu J, Khanna A, Josiah S, Rederstorff M, Zhang MQ, Stamm S.
Author information:
(1)Department of Molecular and Cellular Biochemistry, University of Kentucky,
Lexington, KY, 40536, USA.
We describe a new method that allows cloning of double-stranded RNAs (dsRNAs)
that are generated in RNase protection experiments. We demonstrate that the
mouse C/D box snoRNA MBII-85 (SNORD116) is processed into at least five shorter
RNAs using processing sites near known functional elements of C/D box snoRNAs.
Surprisingly, the majority of cloned RNAs from RNase protection experiments were
derived from endogenous cellular RNA, indicating widespread antisense
expression. The cloned dsRNAs could be mapped to genome areas that show RNA
expression on both DNA strands and partially overlapped with experimentally
determined argonaute-binding sites. The data suggest a conserved processing
pattern for some C/D box snoRNAs and abundant expression of longer, non-coding
RNAs in the cell that can potentially form dsRNAs.
© The Author(s) 2011. Published by Oxford University Press.
DOI: 10.1093/nar/gkr684
PMCID: PMC3239178
PMID: 21880592 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7776900 | 1. Med Hypotheses. 1995 Jan;44(1):39-46. doi: 10.1016/0306-9877(95)90299-6.
Meditation, melatonin and breast/prostate cancer: hypothesis and preliminary
data.
Massion AO(1), Teas J, Hebert JR, Wertheimer MD, Kabat-Zinn J.
Author information:
(1)University of Massachusetts Medical Center, Department of Psychiatry,
Worcester, USA.
The objective of this study was to test the hypothesis that the regular practice
of mindfulness meditation is associated with increased physiological levels of
melatonin. Melatonin may be related to a variety of biologic functions important
in maintaining health and preventing disease, including breast and prostate
cancer. Previous studies have shown melatonin production is photosensitive and
we suggest here that it also may be psychosensitive. A cross-sectional study of
12-hour (20:00-08:00) urinary 6-sulphatoxymelatonin was conducted from which we
analyzed data from 8 women who regularly meditate (RM) and 8 women who do not
meditate (NM). All samples were collected in the homes of study participants.
Volunteers were recruited to provide 12-hour overnight samples of urine. All
subjects collected the samples on one night during the same 1-week period. There
was no explicit intervention. However, all RM were either graduates of, or
teachers in, the University of Massachusetts Stress Reduction and Relaxation
Program. The main outcome measure was the total excretion of urinary
6-sulphatoxymelatonin. Multiple linear regression (Proc GLM in SAS) was
performed to test the effect of meditation (RM vs NM) on 6-sulphatoxymelatonin.
The results of the study were that after controlling for the non-significant
effect of menstrual period interval, we found an effect of meditation group (RM
vs NM: b = 1.983; F = 6.78; p = 0.02) and age (for each integer year: b = 0.169;
F = 8.41; p = 0.01). The conclusion is that study results are consistent with
our hypothesis and indicate that melatonin might be a useful parameter in
testing similar psycho-social interventions.(ABSTRACT TRUNCATED AT 250 WORDS)
DOI: 10.1016/0306-9877(95)90299-6
PMID: 7776900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19878874 | 1. Cancer Cell. 2009 Nov 6;16(5):425-38. doi: 10.1016/j.ccr.2009.09.026.
Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular
carcinoma development through inactivation of the Yap1 oncogene.
Zhou D(1), Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee
JT, Avruch J, Bardeesy N.
Author information:
(1)Department of Molecular Biology, Massachusetts General Hospital, Boston, MA
02114, USA.
Comment in
Cancer Cell. 2009 Nov 6;16(5):363-4. doi: 10.1016/j.ccr.2009.10.008.
Gastroenterology. 2010 Aug;139(2):692-4. doi: 10.1053/j.gastro.2010.06.036.
Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in
Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo
orthologs, are cleaved and constitutively activated in the mouse liver. Combined
Mst1/2 deficiency in the liver results in loss of inhibitory Ser127
phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and
hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines
promotes Yap1 Ser127 phosphorylation and inactivation and abrogates their
tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an
intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show
low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved,
activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor
suppression in liver relevant to human HCC.
DOI: 10.1016/j.ccr.2009.09.026
PMCID: PMC3023165
PMID: 19878874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24304610 | 1. Nutrients. 2013 Dec 4;5(12):4938-49. doi: 10.3390/nu5124938.
Adult cranberry beverage consumers have healthier macronutrient intakes and
measures of body composition compared to non-consumers: National Health and
Nutrition Examination Survey (NHANES) 2005-2008.
Duffey KJ(1), Sutherland LA.
Author information:
(1)Department of Human Nutrition, Foods and Exercise, Virginia Tech, 223 Wallace
Hall, 295 Campus Drive, Blacksburg, VA 24061, USA. [email protected].
Flavonoids, present in high levels in cranberries, are potent bioactives known
for their health-promoting benefits, but cranberry beverages (CB) are not
typically recommended as part of a healthy diet. We examine the association
between CB consumption with macronutrient intake and weight status. Data for US
adults (≥19 years, n = 10,891) were taken from the National Health and Nutrition
Examination Survey (NHANES) Survey 2005-2008. Total CB consumption was measured
over two non-consecutive 24-h dietary recalls. Linear and logistic regression
models adjusting for important covariates were used to examine predicted
differences between CB consumers and non-consumers on macronutrient and
anthropometric outcomes. Results are weighted to be nationally representative.
CB consumers (n = 581) were older (>50 year) non-Hispanic black females. They
consumed an average 221 mL (7.5 oz) CB per day. In fully adjusted models CB
consumers (vs. non-consumers) had higher carbohydrates and total sugars and
lower percent energy from protein and total fat (all p < 0.001), but no
difference in total energy. A significantly higher proportion of CB consumers
were predicted to be normal weight (BMI < 25 kg/m2; p = 0.001) and had to have
lower waist circumferences (p = 0.001). Although there was not a significant
trend across level of CB intake, low and middle level CB consumers compared to
non-consumers were more likely to be normal weight (p < 0.001) and less likely
to be overweight/obese (BMI ≥ 25 kg/m2, p < 0.001). Despite having slightly
higher daily macronutrient intakes, CB consumers have more desirable
anthropometric measures compared to non-consumers.
DOI: 10.3390/nu5124938
PMCID: PMC3875910
PMID: 24304610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24292857 | 1. J Neural Transm (Vienna). 2014 Apr;121(4):391-8. doi:
10.1007/s00702-013-1122-x. Epub 2013 Nov 30.
Deep brain stimulation in critical care conditions.
Franzini A(1), Cordella R, Rizzi M, Marras CE, Messina G, Zorzi G, Caldiroli D.
Author information:
(1)Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico "C. Besta",
Via Celoria 11, 20133, Milan, Italy.
Some neurological conditions require admission to an intensive care unit (ICU)
where deep sedation and mechanical ventilation are administered to improve the
patient's condition. Nevertheless, these treatments are not always helpful in
disease control. At this stage, deep brain stimulation (DBS) could become a
viable alternative in the treatment of critical neurological conditions with
long-lasting clinical benefit. The value of deep brain stimulation has been
investigated in the treatment of patients who had undergone surgical electrode
implants as an emergency procedure to treat acute life-threatening conditions
requiring admission to neurological ICU (NICU). A before-and-after perspective
study was examined of seven patients who were treated with DBS for status
dystonicus (SD) and post-stroke severe hemiballismus. Bilateral globus pallidus
internus (GPi) DBS was performed in five SD patients and unilateral ventralis
oralis anterior and posterior (Voa/Vop) nucleus of the thalamus DBS in two
post-stroke hemiballismus patients. Bilateral GPi-DBS allowed SD resolution in a
time lapse varying from 1 week to 3 months. No clear improvements compared to
the baseline clinical condition were observed. Unilateral Voa/Vop-DBS
intervention controlled hemiballismus after 10 h, and the patient was discharged
in 2 days. The other patient was transferred from the NICU to the neurosurgery
ward after 13 days. No surgical complications were observed in any of the above
procedures. Neurostimulation procedures could represent a valuable choice in
critical care conditions, when involuntary movements are continuous,
life-threatening and refractory to intensive care procedures. DBS is feasible,
safe and effective in selected cases.
DOI: 10.1007/s00702-013-1122-x
PMID: 24292857 [Indexed for MEDLINE] |