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http://www.ncbi.nlm.nih.gov/pubmed/20576619
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1. J Biochem. 2010 Sep;148(3):319-26. doi: 10.1093/jb/mvq069. Epub 2010 Jun 23.
Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug
activity.
Zeng ZL(1), Wu MW, Sun J, Sun YL, Cai YC, Huang YJ, Xian LJ.
Author information:
(1)State Key Laboratory of Oncology in South China, Sun Yat-sen University,
Guangzhou, P.R. China.
The Bmal1 gene plays a key role in controlling circadian rhythms. To better
understand how the Bmal1 gene affects tumour growth and the response to
anti-cancer drugs, we examined the effect of knockdown of Bmal1 by RNAi both in
vitro and in vivo. Down-regulation of Bmal1 gene expression accelerated cell
proliferation in vitro and promoted tumour growth in mice. Suppressing Bmal1
expression in murine colon cancer cells (C26) and fibroblast cells (L929)
decreased apoptosis induced by Etoposid, reduced the distribution of cells in
the G2/M phases treated by Docetaxel and decreased DNA damage induced by
Cisplatin. Loss of Bmal1 reduced the expression of per1, per2, per3, wee1 and
p53. The expression of p21 and c-myc was also altered in certain cell lines.
However, Bmal1 deficiency increased the protein levels of cdc2, cyclin B1,
cyclin D1 and cyclin E. Wee1 and cyclin A expression was minimally altered.
Thus, the circadian clock gene Bmal1 plays a role in regulating tumour cell
apoptosis, cell-cycle progression and DNA damage response and in homoeostasis
regulation. Down-regulation of Bmal1 accelerates the development of tumours and
may influence the response to anti-cancer drugs.
DOI: 10.1093/jb/mvq069
PMID: 20576619 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/24794785
|
1. Heart Lung. 2014 May-Jun;43(3):262-3. doi: 10.1016/j.hrtlng.2014.03.004.
Prolonged anticoagulant activity of rivaroxaban in a polymorbid elderly female
with non-convulsive epileptic state.
Stöllberger C(1), Finsterer J(2).
Author information:
(1)Krankenanstalt Rudolfstiftung, Juchgasse 25, 1030 Wien, Austria. Electronic
address: claudia.stoellberger@chello.at.
(2)Krankenanstalt Rudolfstiftung, Juchgasse 25, 1030 Wien, Austria.
OBJECTIVES AND BACKGROUND: Rivaroxaban, an oral direct factor Xa-inhibitor was
non-inferior to adjusted dose warfarin in the prevention of stroke and embolism
among patients with atrial fibrillation (AF) in the ROCKET-AF trial and has been
approved for stroke prevention in AF.
CASE REPORT: A 88-years-old female (body-mass-index = 19.95) with AF,
hypertension and diabetes mellitus, hospitalized because of heart failure and a
non-convulsive epileptic state, was treated by valproate, mirtazepin, nebivolol,
digitoxin, lisinopril, gliclazide and amlodipine. Irrespective of renal
insufficiency, rivaroxaban 15 mg/d was started. After 3 days rivaroxaban was
stopped because of concerns about the bleeding risk. Coagulation tests 28 h
after rivaroxaban-intake showed INR 2.26, PT 35%, aPTT 38.3 s and anti-Factor
Xa-activity 2.00 U/ml. Explanations for the prolonged anticoagulant activity of
rivaroxaban comprise renal failure, the low body-mass-index, the advanced age
and drug-drug interactions of rivaroxaban with mirtazepin, valproate and
amlodipine.
CONCLUSION: Health care providers should consider renal function, concomitant
medication, polymorbidity and age prior to prescribing rivaroxaban. Care has to
be taken when prescribing rivaroxaban to patients who are different from those
included in the ROCKET AF trial.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.hrtlng.2014.03.004
PMID: 24794785 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16442164
|
1. Prog Lipid Res. 2006 Mar;45(2):91-101. doi: 10.1016/j.plipres.2005.12.001.
Epub 2006 Jan 18.
Cardiolipin metabolism and Barth Syndrome.
Hauff KD(1), Hatch GM.
Author information:
(1)Department of Pharmacology and Therapeutics, Faculty of Medicine, University
of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T6.
Many advances have occurred in the field of Barth Syndrome biology in the 26
years since it was first described as an X-linked cardiomyopathy. Barth Syndrome
is the first human disease recognized in which the primary causative factor is
an alteration in cardiolipin remodeling. Cardiolipin is required for the optimal
function of many proteins within the mitochondria, particularly in the
respiratory chain and is involved in the mitochondrial-mediated apoptotic
process. The appropriate content of cardiolipin appears to be critical for these
functions. Cardiolipin is synthesized de novo in mitochondria and is rapidly
remodeled to produce CL enriched in linoleic acid. The Barth Syndrome gene TAZ
has been identified and expression of the gene yields proteins known as
tafazzins. Mutations in TAZ result in a decrease in tetra-linoleoyl species of
cardiolipin and an accumulation of monolysocardiolipin within cells from Barth
Syndrome patients. Although the protein product of the TAZ gene shows sequence
homology to the glycerolipid acyltransferase family of enzymes, its precise
biochemical function remains to be elucidated. In this review we highlight some
of the recent literature on cardiolipin metabolism and Barth Syndrome.
DOI: 10.1016/j.plipres.2005.12.001
PMID: 16442164 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16857210
|
1. J Mol Biol. 2006 Aug 18;361(3):462-9. doi: 10.1016/j.jmb.2006.06.057. Epub
2006 Jul 5.
Mitochondrial respiratory chain supercomplexes are destabilized in Barth
Syndrome patients.
McKenzie M(1), Lazarou M, Thorburn DR, Ryan MT.
Author information:
(1)Department of Biochemistry, La Trobe University, Melbourne, Australia.
Mutations in the human TAZ gene are associated with Barth Syndrome, an often
fatal X-linked disorder that presents with cardiomyopathy and neutropenia. The
TAZ gene encodes Tafazzin, a putative phospholipid acyltranferase that is
involved in the remodeling of cardiolipin, a phospholipid unique to the inner
mitochondrial membrane. It has been shown that the disruption of the Tafazzin
gene in yeast (Taz1) affects the assembly and stability of respiratory chain
Complex IV and its supercomplex forms. However, the implications of these
results for Barth Syndrome are restricted due to the additional presence of
Complex I in humans that forms a supercomplex with Complexes III and IV. Here,
we investigated the effects of Tafazzin, and hence cardiolipin deficiency in
lymphoblasts from patients with Barth Syndrome, using blue-native polyacrylamide
gel electrophoresis. Digitonin extraction revealed a more labile Complex
I/III(2)/IV supercomplex in mitochondria from Barth Syndrome cells, with Complex
IV dissociating more readily from the supercomplex. The interaction between
Complexes I and III was also less stable, with decreased levels of the Complex
I/III(2) supercomplex. Reduction of Complex I holoenzyme levels was observed
also in the Barth Syndrome patients, with a corresponding decrease in
steady-state subunit levels. We propose that the loss of mature cardiolipin
species in Barth Syndrome results in unstable respiratory chain supercomplexes,
thereby affecting Complex I biogenesis, respiratory activities and subsequent
pathology.
DOI: 10.1016/j.jmb.2006.06.057
PMID: 16857210 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17525233
|
1. Stem Cells. 2007 Sep;25(9):2191-9. doi: 10.1634/stemcells.2007-0203. Epub 2007
May 24.
High histone acetylation and decreased polycomb repressive complex 2 member
levels regulate gene specific transcriptional changes during early embryonic
stem cell differentiation induced by retinoic acid.
Lee ER(1), Murdoch FE, Fritsch MK.
Author information:
(1)Cancer Biology Program, University of Wisconsin-Madison, Madison, Wisconsin
53706, USA.
Histone modifications play a crucial role during embryonic stem (ES) cell
differentiation. During differentiation, binding of polycomb repressive complex
2 (PRC2), which mediates trimethylation of lysine 27 on histone H3 (K27me3), is
lost on developmental genes that are transcriptionally induced. We observed a
global decrease in K27me3 in as little as 3 days after differentiation of mouse
ES cells induced by retinoic acid (RA) treatment. The global levels of the
histone K27 methyltransferase EZH2 also decreased with RA treatment. A loss of
EZH2 binding and K27me3 was observed locally on PRC2 target genes induced after
3 days of RA, including Nestin. In contrast, direct RA-responsive genes that are
rapidly induced, such as Hoxa1, showed a loss of EZH2 binding and K27me3 after
only a few hours of RA treatment. Following differentiation induced by leukemia
inhibitor factor (LIF) withdrawal without RA, Hoxa1 was not transcriptionally
activated. Small interfering RNA-mediated knockdown of EZH2 resulted in loss of
K27me3 during LIF withdrawal, but the Hoxa1 gene remained transcriptionally
silent after loss of this repressive mark. Induction of histone hyperacetylation
overrode the repressive K27me3 modification and resulted in Hoxa1 gene
expression. Together, these data show that there are multiple temporal phases of
derepression of PRC2 target genes during ES cell differentiation and that other
epigenetic marks (specifically, increased acetylation of histones H3 and H4), in
addition to derepression, are important for gene-specific transcriptional
activation. This report demonstrates the temporal interplay of various
epigenetic changes in regulating gene expression during early ES cell
differentiation.
DOI: 10.1634/stemcells.2007-0203
PMID: 17525233 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20981509
|
1. Indian J Pediatr. 2010 Dec;77(12):1432-3. doi: 10.1007/s12098-010-0222-y. Epub
2010 Oct 28.
Barth syndrome: an X-linked cardiomyopathy with a novel mutation.
Aljishi E(1), Ali F.
Author information:
(1)Salmaniya Medical Complex, Manama, Bahrain. ejishi@health.gov.bh
The authors report a 6 yr old boy with Barth syndrome who presented with
cardiomyopathy, neutropenia and hypotonia. Urine gas chromatography showed high
level of 3-methylglutaconic acid. The DNA of both the patient and the mother
showed a heterozygous 3 bp deletion in exon 8 of the tafazzin gene. This
abnormality involves the deletion of the bases TGA starting at cDNA nucleotide
891 (c891_893delTGA), resulting in the absence of glutamic acid at codon 202
from a highly conserved area of the tafazzin protein, consistent with the
diagnosis of Barth syndrome. This is the first case report of Barth syndrome in
Arab population emphasizing the importance of detailed investigations in cases
of hereditary cardiomyopathy.
DOI: 10.1007/s12098-010-0222-y
PMID: 20981509 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24813252
|
1. Nat Med. 2014 Jun;20(6):616-23. doi: 10.1038/nm.3545. Epub 2014 May 11.
Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced
pluripotent stem cell and heart-on-chip technologies.
Wang G(1), McCain ML(2), Yang L(3), He A(4), Pasqualini FS(5), Agarwal A(5),
Yuan H(5), Jiang D(4), Zhang D(4), Zangi L(4), Geva J(4), Roberts AE(6), Ma
Q(4), Ding J(4), Chen J(4), Wang DZ(4), Li K(4), Wang J(7), Wanders RJ(8), Kulik
W(8), Vaz FM(8), Laflamme MA(9), Murry CE(10), Chien KR(11), Kelley RI(12),
Church GM(3), Parker KK(13), Pu WT(14).
Author information:
(1)1] Department of Cardiology, Boston Children's Hospital, Boston,
Massachusetts, USA. [2].
(2)1] Wyss Institute for Biologically Inspired Engineering, School of
Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts,
USA. [2].
(3)1] Wyss Institute for Biologically Inspired Engineering, School of
Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts,
USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts,
USA.
(4)Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts,
USA.
(5)Wyss Institute for Biologically Inspired Engineering, School of Engineering
and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
(6)1] Department of Cardiology, Boston Children's Hospital, Boston,
Massachusetts, USA. [2] Department of Medicine, Division of Genetics, Boston
Children's Hospital, Boston, Massachusetts, USA.
(7)1] Allele Biotechnology & Pharmaceuticals, Inc., San Diego, California, USA.
[2] Department of Photobiology and Bioengineering, The Scintillon Institute, San
Diego, California, USA.
(8)Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic
Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
(9)Department of Pathology, Center for Cardiovascular Biology and Institute for
Stem Cell and Regenerative Medicine, University of Washington, Seattle,
Washington, USA.
(10)1] Department of Pathology, Center for Cardiovascular Biology and Institute
for Stem Cell and Regenerative Medicine, University of Washington, Seattle,
Washington, USA. [2] Department of Bioengineering, Center for Cardiovascular
Biology, Institute for Stem Cell and Regenerative Medicine, University of
Washington, Seattle, Washington, USA. [3] Department of Medicine and Cardiology,
Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative
Medicine, University of Washington, Seattle, Washington, USA.
(11)Department of Cell and Molecular Biology and Medicine, Karolinska
Institutet, Stockholm, Sweden.
(12)Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland, USA.
(13)1] Wyss Institute for Biologically Inspired Engineering, School of
Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts,
USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge,
Massachusetts, USA.
(14)1] Department of Cardiology, Boston Children's Hospital, Boston,
Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University,
Cambridge, Massachusetts, USA.
Comment in
Nat Med. 2014 Jun;20(6):585-6. doi: 10.1038/nm.3592.
Cell Stem Cell. 2014 Jul 3;15(1):9-11. doi: 10.1016/j.stem.2014.06.015.
Study of monogenic mitochondrial cardiomyopathies may yield insights into
mitochondrial roles in cardiac development and disease. Here, we combined
patient-derived and genetically engineered induced pluripotent stem cells
(iPSCs) with tissue engineering to elucidate the pathophysiology underlying the
cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by
mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived
cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional
abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and
irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted
weakly. Gene replacement and genome editing demonstrated that TAZ mutation is
necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial
contraction abnormalities occurred in the context of normal whole-cell ATP
levels. Excess levels of reactive oxygen species mechanistically linked TAZ
mutation to impaired cardiomyocyte function. Our study provides new insights
into the pathogenesis of Barth syndrome, suggests new treatment strategies and
advances iPSC-based in vitro modeling of cardiomyopathy.
DOI: 10.1038/nm.3545
PMCID: PMC4172922
PMID: 24813252 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19723660
|
1. Cancer Res. 2009 Sep 15;69(18):7412-21. doi: 10.1158/0008-5472.CAN-09-0116.
Epub 2009 Sep 1.
DNMT1 and DNMT3B modulate distinct polycomb-mediated histone modifications in
colon cancer.
Jin B(1), Yao B, Li JL, Fields CR, Delmas AL, Liu C, Robertson KD.
Author information:
(1)Department of Biochemistry and Molecular Biology and Cancer Research Center,
Medical College of Georgia, Augusta, Georgia 30912, USA.
DNA methylation patterns are established and maintained by three DNA
methyltransferases (DNMT): DNMT1, DNMT3A, and DNMT3B. Although essential for
development, methylation patterns are frequently disrupted in cancer and
contribute directly to carcinogenesis. Recent studies linking polycomb group
repression complexes (PRC1 and PRC2) to the DNMTs have begun to shed light on
how methylation is targeted. We identified previously a panel of genes regulated
by DNMT3B. Here, we compare these with known polycomb group targets to show that
approximately 47% of DNMT3B regulated genes are also bound by PRC1 or PRC2. We
chose 44 genes coregulated by DNMT3B and PRC1/PRC2 to test whether these
criteria would accurately identify novel targets of epigenetic silencing in
colon cancer. Using reverse transcription-PCR, bisulfite genomic sequencing, and
pyrosequencing, we show that the majority of these genes are frequently silenced
in colorectal cancer cell lines and primary tumors. Some of these, including
HAND1, HMX2, and SIX3, repressed cell growth. Finally, we analyzed the histone
code, DNMT1, DNMT3B, and PRC2 binding by chromatin immunoprecipitation at
epigenetically silenced genes to reveal a novel link between DNMT3B and the mark
mediated by PRC1. Taken together, these studies suggest that patterns of
epigenetic modifiers and the histone code influence the propensity of a gene to
become hypermethylated in cancer and that DNMT3B plays an important role in
regulating PRC1 function.
DOI: 10.1158/0008-5472.CAN-09-0116
PMCID: PMC2745494
PMID: 19723660 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21055175
|
1. Zhonghua Bing Li Xue Za Zhi. 2010 Jul;39(7):463-6.
[Localization and expression of CLIC1 in hepatocarcinoma ascites cell lines with
high or low potentials of lymphatic spread].
[Article in Chinese]
Song MY(1), Tang JW, Sun MZ, Liu SQ, Wang B.
Author information:
(1)Department of Pathology, Dalian Medical University, Dalian 116044, China.
OBJECTIVE: To study the localization and expression of CLIC1 in mouse
hepatocarcinoma ascites cell lines with different metastatic potentials.
METHODS: Mouse hepatocarcinoma ascites models (a high potential of lymphatic
metastasis cell line-Hca-F, and a low potential of lymphatic metastasis cell
line-Hca-P) were investigated using fluorescent two-dimensional difference-gel
electrophoresis (2-D DIGE) and mass spectrometry for detecting the localization
and expression of CLIC1. Immunofluorescence, immunocytochemistry and Western
blot were used to assess CLIC1 protein status in the two cell lines.
RESULTS: CLIC1 expression was obtained in the cytoplasm and plasma membrane of
cells in both cell lines. 2-D DIGE showed that CLIC1 was overexpressed in Hca-F
cells, 1.6 folds higher than that of the Hca-P cells. Hca-F cells also had a
higher integral membrane CLIC1 in the Hca-P cells.
CONCLUSIONS: Although CLIC1 expression is detected in both Hca-F and Hca-P cell
lines, a higher protein expression level is present in Hca-F cells. CLIC1 may
play an important role in tumor metastasis.
PMID: 21055175 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20385584
|
1. Nucleic Acids Res. 2010 Aug;38(15):4958-69. doi: 10.1093/nar/gkq244. Epub 2010
Apr 12.
Characterization of an antagonistic switch between histone H3 lysine 27
methylation and acetylation in the transcriptional regulation of Polycomb group
target genes.
Pasini D(1), Malatesta M, Jung HR, Walfridsson J, Willer A, Olsson L, Skotte J,
Wutz A, Porse B, Jensen ON, Helin K.
Author information:
(1)Biotech Research and Innovation Centre (BRIC), University of Copenhagen,
Copenhagen, Denmark.
Erratum in
Nucleic Acids Res. 2021 Sep 7;49(15):9000-9001. doi: 10.1093/nar/gkab625.
Polycomb group (PcG) proteins are transcriptional repressors, which regulate
proliferation and cell fate decisions during development, and their deregulated
expression is a frequent event in human tumours. The Polycomb repressive complex
2 (PRC2) catalyzes trimethylation (me3) of histone H3 lysine 27 (K27), and it is
believed that this activity mediates transcriptional repression. Despite the
recent progress in understanding PcG function, the molecular mechanisms by which
the PcG proteins repress transcription, as well as the mechanisms that lead to
the activation of PcG target genes are poorly understood. To gain insight into
these mechanisms, we have determined the global changes in histone modifications
in embryonic stem (ES) cells lacking the PcG protein Suz12 that is essential for
PRC2 activity. We show that loss of PRC2 activity results in a global increase
in H3K27 acetylation. The methylation to acetylation switch correlates with the
transcriptional activation of PcG target genes, both during ES cell
differentiation and in MLL-AF9-transduced hematopoietic stem cells. Moreover, we
provide evidence that the acetylation of H3K27 is catalyzed by the
acetyltransferases p300 and CBP. Based on these data, we propose that the PcG
proteins in part repress transcription by preventing the binding of
acetyltransferases to PcG target genes.
DOI: 10.1093/nar/gkq244
PMCID: PMC2926606
PMID: 20385584 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24895454
|
1. Circulation. 2014 Jul 8;130(2):138-46. doi: 10.1161/CIRCULATIONAHA.113.005008.
Epub 2014 Jun 3.
Efficacy and safety of rivaroxaban compared with warfarin among elderly patients
with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct
Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation (ROCKET AF).
Halperin JL(1), Hankey GJ(2), Wojdyla DM(2), Piccini JP(2), Lokhnygina Y(2),
Patel MR(2), Breithardt G(2), Singer DE(2), Becker RC(2), Hacke W(2), Paolini
JF(2), Nessel CC(2), Mahaffey KW(2), Califf RM(2), Fox KA(2); ROCKET AF Steering
Committee and Investigators.
Collaborators: Anderson J, Bedwell N, Bilsker M, Bruce G, Agah R, DeSantis M,
Eisenberg S, Flores A, Herzog W, Klein S, Snyder H, Krueger S, Almaguer E, Lavie
E, Lee C, Mallis G, Modi M, Woodworth G, Niazi I, Peart B, Sundaram S, Snoddy B,
Sotolongo R, Moloney J, Vijayaraghavan K, Whittier F, Yellen L, Banerjee S,
Lustgarten D, Suresh D, Gelernt M, Levinson L, Ghanekar R, Niazi I, Kneller G,
Hall C, Fadl Y, Suresh D, Pirwitz M, French W, Mayer N, Pugeda J, Steel K, Mody
F, Malik A, Chandna H, Go A, Emlein G, Bowden W, Moscoso R, Hodson R, Berk M,
Pan D, Pappas J, Orchard R, Lynchard G, Vijay N, Khan W, El Khadra M, Antonishen
M, Cucher F, Staab M, Zebrack J, Borromeo S 3rd, Heilman J, Chaturvedi S, Makam
S, Turk S, Hyers T, Williams G, Labroo A, Gill S, Myears D, Weinstein J, Shanes
J, Chandrashekhar Y, Shah S, Reiter W, Logemann T, Almquist A, Bhagwat R, Tak T,
Shen-Ling J, Patel P, Artis A, Arouni A, Lauer M, Kinney K, Elsen J, Roan P,
Villafria R, Sumpter M, Ip J, Welka S, Schifferdecker B, Sandoval R, Speirs S,
Jones A, Haldis T, Kazmierski J, Sutherland J, Dietrich D, Telfer E, Berry J,
McElveen A, Russell J, Sackett M, Antonios N, Smith D, Vora K, Kirby A, Lui H,
Mego D, Ziada K, Navas J, Taussig A, Koren M, Vogel C, Saba F, Parrott C,
Schneider R, Shirwany A, Rubin M, Treasure C 2nd, Bertolet B, Chang M, Langberg
J, Becker R, Cohen Y, McGrew F, White J, Arzola F, Zelenka J, Tannenbaum A,
Fernandes V, Jamnadas P, Agamasu J, Collins B, Jauch W, Sasseen B, Hotchkiss D,
Abadier R, Osunkoya A, Schlau A, Chappel C, Foster M, Braun E, Mostel E, Capo J,
Ashchi M, Howard V, Albirini A, Burger A, Rolston D, Staniloae C, Bacon J,
Wiseman A, McGarvey J Jr, Sonel A, Hamroff G, Chang D, Daboul N, Broderick G,
Meholick A, Corbelli J, Silverman R, Raffetto J, Fishberg R, Georgeson S, Held
J, Seidner M, Saint-Jacques H, Heitner J, Kutalek S, Friedlander I, Hutchinson
B, Walia J, Kondo N, Smiley N, Blitz L, Dale H, Sulman S, Szulawski I, Modares
F, Martin R, Nahhas A, Renzi M, Akyea-Djamson A, Alfieri A, Sandhu J, Voyce S,
Amaram S, Meyerrose G, Shoukfeh M, Lee F, Villegas B, Idowu O, Khera A, Sam C,
Vo A, Lieber I, Smith T, Awan N, Tsai C, Ganim R, Alzaghrini G, Pitt W, Shepherd
A, Tang S, Go A, Stoltz S, Nelson W, Cox S, Meymandi S, Melucci M, Thomas G,
Gogia H, Machell C, Chandrasekaran S, Brown C, Jetty P, Miller G, Dykstra G,
Jaffrani N, Zakhary B, Caruso A, Zolty R, Fox D, Jacobs G, Lebenthal M,
Mukherjee S, Zimetbaum P, Kingsley J, Jones R, Robinson V, Kenton D, Usedom J,
Williams S, Snipes C, Wilson V, Hasty R, Shoemaker J, Robinson V, Donahue M,
Al-Saghir Y, Thomsen E, Yarows S, Chastain S, McLaughlin P, Wakham M, Shrestha
D, Simmons J, Fisher D, Seymour Z, Frandsen B, First B, Sharpe C, Popeil L,
Guthrie R, Hunter J, Alvarado O, Sandberg J, Gutman N, Belber A, Arkhipov M,
Ballyzek M, Baranov A, Barbarash O, Barbarich V, Belenky D, Berkovich O, Bokarev
I, Boyarkin M, Vaniev S, Volkova E, Gratsiansky N, Demin A, Zadionchenko V,
Zateyshchikov D, Zrazhevsky K, Mazaev V, Martynov A, Mikhailov S, Mkrtchian V,
Novozhenov V, Raskina T, Rebrov A, Sanina N, Simanekov V, Sitnikova M,
Smolenskaya O, Stryuk R, Storozhakov G, Tankhilevich B, Tereschenko S, Khokhlov
A, Khrustalev O, Chernov S, Shvarts Y, Shubik Y, Shulman V, Yakushin S, Bugrova
O, Ivleva A, Libis R, Khozyainova N, Maslov S, Baranova E, Sherenkov A, Libov I,
Lusov V, Chumakova G, Kuznetsov V, Ryamzina I, Reshetko O, Boldueva S, Alekseeva
N, Novikova T, Dvornikov V, Idrisova E, Shostak N, Yarokhno N, Tebloev K,
Treshkur T, Mazurov V, Loktin E, Sedavnyh I, Alexeeva O, Yakhontova P, Repin A,
Izmozherova N, Kostenko V, Fokin A, Ketova G, Kouz S, Leader R, Ayala-Paredes F,
Luton R, Ma P, Pandey S, Pesant Y, Senior R, Vertes G, Bell A, Crowley D, Vizel
S, Lasko B, Landry D, Berger L, Heath J, Bessoudo R, Ling M, Tellier G,
Berlingieri J, Kafka H, Hill L, Mazza G, O'Mahony W, Chilvers M, O'Mahony M,
Newman D, Newman D, Newman D, Silagy S, Heffernan M, Bennett M, Bhesania T,
Rockman G, Ng K, Kalra B, Meneses G, Liang W, Cheung M, Kozak J, Pugen G,
Vavougios J, Kates M, Nunes-Vaz C, Jaffer S, Orfi J, Faiers A, Chung C, Felsen
S, Bergman S, Bernstein I, Brownscombe L, Stockdill J, Silver E, Ezekiel D,
Jagan N, Khurana M, Reisler H, Goldman H, Maung T, Wong F, Gillis G, Vexler R,
Goldberg B, Luterman M, Gould D, Coutu B, Ouellet A, MacDonald P, Jones M,
Collette R, Chong P, Fargher T, St- Maurice F, Fortin C, Chehayeb R, Proulx G,
Roy R, Liutkus J, Syan G, Rupka D, Lichtenstein T, Kooy J, Papastergiou D,
Lubelsky B, Doyle W, Rajakumar A, Cha J, Choudhry A, Bhamjee H, Mawji A,
Durfresne M, Constance C, Mutrie J, Najarali A, Warren R, Mucha M, Borts D, Nord
P, Carrier S, Dawood M, Sabe-Affaki G, Archibald J, Abram N, Teitelbaum E,
Ebrahim I, Siebert R, van Zyl L, Theron H, Lloyd E, Sommers R, Podgorski G,
Steingo L, Dalby A, Bayat J, Herbst L, Bester F, Corbett C, Bennett J, Roodt A,
Roux J, Abelson M, Mohamed Z, Nortje H, Silva A, Nikolaides K, Liagkas K,
Papasteriadis E, Achimastos A, Koliopoulos N, Trikas A, Manolis A, Ruiter J,
Basart D, Crijns H, Withagen A, Janssen M, Van Langeveld R, van Gelder I, Hamer
B, Van Der Heijden R, Hertzeberger D, Van Hessen M, Pieterse M, Groutars R,
Kuijper A, De Ruiter G, van Boven A, Hoogslag P, Kragten H, Thijssen H, Veldkamp
R, Scavee C, Heidbuchel H, Debruyne P, Deruyter B, El Ali H, Goethals M, Cytryn
R, Striekwold H, De Wolf L, Goethals P, Provenier F, Hellemans S, Galinier M,
Coisne D, Koenig A, Galley D, Destrac S, Leduc J, Rifai A, Citron B, Ellie E,
Fournier P, Steg G, Landel R, Robinson A, Ziegler F, Boulliat J, Zuber M, Vida
M, Basilio E, Lopez M, Íñiguez C, Alonso L, Gibanel M, Martinez J, Iglesias F,
Vera P, Cortada J, Houbani A, Merino J, Preciado F, Balaguer J, Galarza J, Rubio
A, Fontcuberta J, Marti J, Juanatey J, Del Campo R, Vivanco G, Garcia P, Pelayo
M, Lippai J, Zamolyi K, Károly T, Vertes A, Nagy A, Kosa I, Janosi A, Lupkovics
G, Kalo E, Forster T, Kis E, Tenczer J, Bereczki D, Komoly S, Csanyi A, Kiss R,
Valikovics A, Dioszeghy P, Masini F, Terrosu P, Cirrincione V, Marabotti C,
Cosmi F, Salvioni A, Binetti G, Piovaccari G, Nassiacos D, Boriani G, Calvi V,
De Caterina R, Pengo V, Parati G, Carolei A, D'Angelo A, Di Biase M, Fattore L,
Agnelli G, Merlini P, Furlan M, Rasura M, Gandolfo C, Ageno W, Piovella F,
Micieli G, Cinteza M, Fierbinteanu C, Natase-Melicovici D, Ionescu D, Macarie C,
Nanea I, Radoi M, Tatu-Chitoiu G, Dragulescu S, Tudose A, Militaru C, Bengus C,
Ungureanu G, Tau A, Popa V, Pirvu O, Bojinca M, Sipciu D, Popescu M, Chiru M,
Vinereanu D, Tudoran M, Cojocaru T, Vintila M, Aron G, Petrascu O, Bolohan F,
Baumgartner R, Sekoranja L, Vojacek J, Lacnak B, Kellnerova I, Dunaj M, Cihalik
C, Janota T, Janousek J, Bouchal P, Spacek R, Siruckova J, Heinc P, Vojtisek P,
Pirchala M, Malecha J, Padour F, Linhart A, Mandysova E, Jandik J, Zidkova E,
Sipula D, Ostadal P, Polasek R, Stransky V, Marcinek G, Rysava D, Osmancik P,
Huber K, Drexel H, Brainin M, Eichinger-Hasenauer S, Lang W, Pilger E, Moriarty
A, Hudson I, Tang K, Cleland J, MacWalter R, Cooke J, McInnes G, Durairaj R,
MacLeod M, Murdoch D, Kadr H, Lip G, Andrews R, Hunt B, Jackson P, MacLeod M,
Roffe C, Syed H, Bath P, Coyle J, Kelly D, Stender S, Torp- Pedersen C, Tuxen C,
Jensen G, Melchior T, Klarlund K, Dahlstrom C, Nielsen T, Nielsen E,
Bronnum-Schou J, Sykulski R, Blomstrom P, Lindholm C, Wallen T, Nilsson C,
Bertholds E, Carlsater J, Sirnes P, Elle S, Risberg K, Furuseth K, Skag A,
Hoivik H, Landmark N, Kjaernli T, Berg-Johansen J, Gradek G, Drzewiecki A, Pluta
W, Szwed H, Trusz-Gluza M, Ogorek M, Loboz-Grudzien K, Ruszkowski P, Sciborski
R, Kopaczewski J, Jaworska K, Kubica J, Opolski G, Hoffman A, Krzciuk M,
Sinkiewicz W, Piotrowski W, Kolodziej P, Goszczynska M, Rynkiewicz A, Chojnowska
L, Lewczuk J, Biedrzycka M, Piepiorka M, Kowal J, Karczmarczyk A, Pruszczyk P,
Tendera M, Gaciong Z, Krzeminska-Pakula M, Kornacewicz-Jach Z, Kania G,
Brachmann J, Lawall H, Guelker H, Spitzer S, Moebius-Winkler S, Dempfle C, Bode
C, Darius H, Genth-Zotz S, Sommer S, Roehnisch J, Strasser R, Daenschel W,
Schwencke C, Dahl J, Meuser M, Behrens-Spandau S, Behrens-Humbold S, Muegge A,
Schoen N, Grooterhorst P, Ebert H, Kraemer A, Kohler B, Taggeselle J, Claus G,
Sarnighausen H, Al-Zoebi A, Schroeder T, Weissbrodt M, Lange R, Gabelmann M,
Kaeaeb S, Doerr M, Boscher D, Bosch R, Sonntag F, Bauknecht C, Omran H, Leicht
M, Veltkamp R, Hohensee H, Dieckmann H, Winkelmann B, Bernhardt P, Schnabel A,
Kadel C, Proskynitopoulos N, Seidl K, Schellong S, Rios C, Guevara C, Coloma R,
Torrejon H, Galvan J, Silva J, Gallegos J, Mendoza A, Negron S, Watanabe L,
Medina F, Carrilo L, Lopez H, Rodriguez I, Leiva-Pons J, Velasco A,
Villarreal-Careaga J, De los Rios M, Gamba M, Esperon G, Villeda E, Guerrero A,
Alvariqueta A, Amuchastegui M, Bluguermann J, Caime G, Cuneo C, Gabito A, Brasca
D, Hominal M, Jure H, Luquez H, Montana O, Piskorz D, Listorti S, Serra J, Sessa
H, Varini S, Vita N, Aiub J, MacKinnon I, Chekherdemian S, Castagnino J, Canella
J, Sgammini H, Escudero A, Albina G, Rapallo C, Balparda C, Chahin M, Fuentealba
V, Riccitelli M, Casabe J, Marquez L, Kevorkian R, Cuadrado J, Dran R, Muntaner
J, Gonzalez M, Cartasegna L, Hasbani E, Hrabar A, Sanchez A, Vogel D, Hershson
A, Avezum A, Jaber J, Leaes P, Bozza A, Filho A, Filho P, Jorge J, Maia L,
Manenti E, Mora R Jr, Neto J, Precoma D, Rabelo A, Rocha J, Rossi P, Saraiva J,
Zimerman L, Bodanese L, Figueiredo E, de Souza W, Braga J, Alessi S, Gomes M,
Silva R, Teixeira M, Costa F, Motta M, Filho D, Reis G, Garbelini B Jr,
Zimmermann S, Barretto A, Dohmann H, Filho J, Ghorayeb N, Borelli F, dos Santos
F, Prudente M, Vejar M, Lanas F, Del Pino R, Potthoff S, Charme G, Aguirre A,
Saldana A, Garces E, Bunster L, Figueroa H, Olivares C, Raffo C, Vergara E,
Sepulveda P, Jano G, Alvarado J, Suarez R, Urina M, Perez G, Quintero A, Pava L,
Lopez R, Luengas C, Hernandez E, Sanchez D, Poveda C, Coronel J, Beltran R,
Jaramillo C, Pardo J, Negretti C, Isea J, Vergara G, Morr I, Sim K, Ahmad W,
Yusof Z, Rosman A, Basri H, Thompson P, Jeffery I, Purnell P, Roberts-Thomson P,
Heddle W, Waites J, Walters D, Amerena J, Challa P, Karrasch J, Lowy A,
Fitzpatrick D, Parsons M, Phan T, Karrasch J, Karrasch J, Bladin C, Donnan G,
Aroney G, Gerraty R, Anderson C, Blombery P, Martin P, Wijeratne K, Cross D,
Crimmins D, Packham D, Jackson D, Chua W, Merino R, Magno M, Tirador L, Batalla
E, Manalo C, Uy N, Ebo G, Reyes E, Bernan A, Richards M, Hart H, Mann S, Fisher
R, Stewart R, Wilkins G, Barber A, Tan R, Ong H, Singh R, Sukonthasarn A,
Tanomsup S, Krittayaphong R, Piamsomboon C, Piyayotai D, Sunsaneewitayakul B,
Baek S, Seo H, Rim S, Kim C, Kim K, Ryu K, Jo S, Tahk S, Lee H, Kim C, Kim Y,
Shin D, Choi Y, Chung N, Namgung J, Kim C, Hong T, Shin W, Jin S, Yan X, Fu G,
Lu G, Yang K, Xu D, Chen J, Liu J, Wu S, Song J, Liao Y, Xu B, Li Z, Ma S, Yin
Y, Zhao Y, Hu D, Ma C, Ma J, Sun J, Li H, Hong X, Yu B, Lu Q, Yang J, Wu Z, Li
Y, Huang Y, Wang Y, Liu M, Cheng Y, Yang T, Chen K, Wang H, Yuan Z, Wang J, Zeng
Z, Chen Y, Yavuzgil O, Kozan O, Etemoglu M, Diker E, Belgi A, Ceyhan C, Cin V,
Yilmaz O, Ata N, Altunkeser B, Agir A, Karadede A, Topsakal R, Gulati R,
Madhavan A, Jain S, Oomman A, Janorkar S, Kumar P, Naik A, Thacker H, Rajasekhar
V, Reddy R, Keshavamurthy C, Jain P, Gowdappa B, Gadkari M, Abhyankar A, Babu B,
Vydianathan P, Sinha S, Garg N, Rao S, Gautam P, Chockalingam K, Kumbla M,
Panwar R, Banker D, Kaste M, Jäkälä P, Roine R, Mihov A, Raev D, Yordanova V,
Dimitrova S, Benov H, Tsanova V, Kyolean M, Marchev S, Stoikov A, Zdravkov N,
Ramshev K, Krastev A, Stamenova P, Angelova I, Pencheva G, Grigorova V,
Petrauskiene B, Skripkauskiene I, Raugaliene R, Norkiene S, Mazutavicius R,
Kavoliuniene A, Aidietiene S, Aganauskiene J, Dailydkiene A, Marcinkeviciene J,
Grigoniene L, Anusauskiene J, Kavaliauskiene R, Lizogub V, Rudenko L, Tseluyko
V, Voronkov L, Sychov O, Svyshchenko Y, Sirenko Y, Serkova V, Seredyuk N,
Pertseva T, Netyazhenko V, Lishnevska V, Kupchynska O, Koval O, Koshukova G,
Karpenko O, Grishyna O, Faynyk A, Dzyak G, Dyadyk O, Yena L, Volkov V, Rudyk I,
Kopytsya M, Kononenko L, Amosova K, Zhurba S, Kazimirko V, Iuzkiv I, Shershnyova
O, Khomazyuk T, Batushkin V, Vykhovanyuk I, Popik G, Skrebkov V, Skurtov A,
Mishchenko T, Lytvynenko N, Sokolova L, Vatutin M, Shved M, Rebrov B, Kadina L,
Vajda M, Ursol G, Zheleznyy V, Vysochanska T, Gozhenko A, Fan K, Ho D, Tse H, Yu
C, Wong L, Yeh H, Pai P, Hsieh I, Huang C, Hsieh Y, Yin W, Tsai L, Huang T, Chen
C, Chiang F, Ueng K, Charng M, Yeh H, Marmor A, Katz A, Butnaru A, Lewis B,
Eldar M, Rosenhack S, Elias N, Koifman B, Shochat M, Swissa M, Zimlichman R,
Bental T, Weiss A, Ganam R, Elias M, Nseir W, Oliven A, Brenner B, Dayan M.
Author information:
(1)From Icahn School of Medicine at Mount Sinai, New York, NY (J.L.H.); School
of Medicine and Pharmacology, University of Western Australia School of Medicine
and Pharmacology, Perth, Australia (G.J.H.); Duke Clinical Research Institute,
Duke University Medical Center, Durham, NC (D.M.W., J.P.P., Y.L., M.R.P.);
University of Münster, Münster, Germany (G.B.); Massachusetts General Hospital
and Harvard Medical School, Boston, MA (D.E.S.); University of Cincinnati
College of Medicine, Cincinnati, OH (R.C.B.); Ruprecht-Karls University,
Heidelberg, Germany (W.H.); Cerenis Therapeutics, Labege, France (J.F.P.);
Janssen Research and Development, Raritan, NJ (C.C.N.); Stanford University
School of Medicine, Stanford, CA (K.W.M.); Duke Translational Medicine
Institute, Duke University Medical Center, Durham, NC (R.M.C.); and University
of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
(K.A.A.F.). jonathan.halperin@mssm.edu.
(2)From Icahn School of Medicine at Mount Sinai, New York, NY (J.L.H.); School
of Medicine and Pharmacology, University of Western Australia School of Medicine
and Pharmacology, Perth, Australia (G.J.H.); Duke Clinical Research Institute,
Duke University Medical Center, Durham, NC (D.M.W., J.P.P., Y.L., M.R.P.);
University of Münster, Münster, Germany (G.B.); Massachusetts General Hospital
and Harvard Medical School, Boston, MA (D.E.S.); University of Cincinnati
College of Medicine, Cincinnati, OH (R.C.B.); Ruprecht-Karls University,
Heidelberg, Germany (W.H.); Cerenis Therapeutics, Labege, France (J.F.P.);
Janssen Research and Development, Raritan, NJ (C.C.N.); Stanford University
School of Medicine, Stanford, CA (K.W.M.); Duke Translational Medicine
Institute, Duke University Medical Center, Durham, NC (R.M.C.); and University
of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
(K.A.A.F.).
Erratum in
Circulation. 2018 Dec 18;138(25):e783. doi: 10.1161/CIR.0000000000000637.
Comment in
Circulation. 2014 Jul 8;130(2):129-31. doi:
10.1161/CIRCULATIONAHA.114.010873.
Ann Intern Med. 2014 Nov 18;161(10):JC5. doi:
10.7326/0003-4819-161-10-201411180-02005.
BACKGROUND: Nonvalvular atrial fibrillation is common in elderly patients, who
face an elevated risk of stroke but difficulty sustaining warfarin treatment.
The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the
Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin
K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation
(ROCKET AF). This prespecified secondary analysis compares outcomes in older and
younger patients.
METHODS AND RESULTS: There were 6229 patients (44%) aged ≥75 years with atrial
fibrillation and ≥2 stroke risk factors randomized to warfarin (target
international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if
creatinine clearance <50 mL/min), double blind. The primary end point was stroke
and systemic embolism by intention to treat. Over 10 866 patient-years, older
participants had more primary events (2.57% versus 2.05%/100 patient-years;
P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001).
Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban
versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence
interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years;
hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as
were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin
per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34;
<75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95%
confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates
were similar in both age groups; there was no interaction between age and
rivaroxaban response.
CONCLUSIONS: Elderly patients had higher stroke and major bleeding rates than
younger patients, but the efficacy and safety of rivaroxaban relative to
warfarin did not differ with age, supporting rivaroxaban as an alternative for
the elderly.
© 2014 American Heart Association, Inc.
DOI: 10.1161/CIRCULATIONAHA.113.005008
PMID: 24895454 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18820470
|
1. Fly (Austin). 2007 May-Jun;1(3):164-71. doi: 10.4161/fly.4717. Epub 2007 May
9.
Accentuate the negative: proteome comparisons using the negative proteome
database.
Reiter LT(1), Do LH, Fischer MS, Hong NA, Bier E.
Author information:
(1)Section of Cell and Developmental Biology, University of California, San
Diego, La Jolla, California 92093-0349, USA.
The availability of complete genome sequence information for diverse organisms
including model genetic organisms has ushered in a new era of protein sequence
comparisons making it possible to search for commonalities among entire
proteomes using the Basic Local Alignment Search Tool (BLAST). Although the
identification and analysis of proteins shared by humans and model organisms has
proven an invaluable tool to understanding gene function, the sets of proteins
unique to a given model organism's proteome have remained largely unexplored. We
have constructed a searchable database that allows biologists to identify
proteins unique to a given proteome. The Negative Proteome Database (NPD) is
populated with pair-wise protein sequence comparisons between each of the
following proteomes: Homo sapiens, Mus musculus, Drosophila melanogaster,
Caenorhabditis elegans, Saccharomyces cerevisiae, Dictyostelium discoideum,
Chlamydomonus reinhardti, Escherichia coli K12, Arabidopsis thaliana and
Methanoscarcina acetivorans. Our analysis of negative proteome datasets using
the NPD has thus far revealed 107 proteins in humans that may be involved in
motile cilia function, 1628 potential pesticide target proteins in flies, 659
proteins shared by flies and humans that are not represented in the less
neurologically complex worm proteome, and 180 nuclear encoded human disease
associated proteins that are absent from the fly proteome. The NPD is the only
online resource where users can quickly perform complex negative and positive
comparisons of model organism proteomes. We anticipate that the NPD and the
adaptable algorithm which can readily be used to duplicate this analysis on
custom sets of proteomes will be an invaluable tool in the investigation of
organism specific protein sets.
DOI: 10.4161/fly.4717
PMID: 18820470 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23869941
|
1. J Med Econ. 2013 Sep;16(9):1163-8. doi: 10.3111/13696998.2013.826664. Epub
2013 Aug 8.
Medical costs in the US of clinical events associated with oral anticoagulant
(OAC) use compared to warfarin among non-valvular atrial fibrillation patients
≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.
Deitelzweig S(1), Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, Graham J.
Author information:
(1)Ochsner Clinic Foundation, New Orleans, LA, USA. sdeitelzweig@ochsner.org
OBJECTIVES: Based on clinical trials the oral anticoagulants (OACs) apixaban,
dabigatran, and rivaroxaban are efficacious for reducing stroke risk for
non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials,
this study evaluated the medical costs for clinical events among NVAF patients
≥75 and <75 years of age treated with individual OACs vs warfarin.
METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e.,
clinical events) among NVAF patients receiving warfarin or each of the OACs were
determined for NVAF populations aged ≥75 years and <75 years of age from the OAC
vs warfarin trials. One-year incremental costs among patients with clinical
events were obtained from published literature and inflation adjusted to 2010
costs. Medical costs, excluding medication costs, for clinical events associated
with each OAC and warfarin were then estimated and compared.
RESULTS: Among NVAF patients aged ≥75, compared to warfarin, use of either
apixaban or rivaroxaban was associated with a reduction in medical costs per
patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was
associated with increased medical costs of $180 per patient year. Among NVAF
patients <75 years of age medical costs per patient year were estimated to be
reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban,
respectively, in comparison to warfarin.
LIMITATIONS: This economic analysis was based on clinical trial data and,
therefore, the direct application of the results to routine clinical practice
will require further assessment.
CONCLUSIONS: Difference in medical costs between OAC and warfarin treated NVAF
patients vary by age group and individual OACs. Although reductions in medical
costs for NVAF patients aged ≥75 and <75 were observed for those using either
apixaban or rivaroxaban vs warfarin, the reductions were greater per patient
year for both the older and younger NVAF populations using apixaban.
DOI: 10.3111/13696998.2013.826664
PMID: 23869941 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23954611
|
1. J Stroke Cerebrovasc Dis. 2014 Feb;23(2):379-83. doi:
10.1016/j.jstrokecerebrovasdis.2013.07.021. Epub 2013 Aug 15.
Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial
fibrillation in relation to the CHADS2 score: a subgroup analysis of the
J-ROCKET AF trial.
Hori M(1), Matsumoto M(2), Tanahashi N(3), Momomura S(4), Uchiyama S(5), Goto
S(6), Izumi T(7), Koretsune Y(8), Kajikawa M(9), Kato M(9), Ueda H(9), Iekushi
K(10), Yamanaka S(9), Tajiri M(9); J-ROCKET AF Study Investigators.
Author information:
(1)Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
(2)Department of Clinical Neuroscience and Therapeutics, Hiroshima University,
Hiroshima, Japan.
(3)Department of Neurology, Saitama Medical University International Medical
Center, Saitama, Japan.
(4)Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical
University, Saitama, Japan.
(5)Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
(6)Department of Medicine (Cardiology), Tokai University School of Medicine,
Tokyo, Japan.
(7)Department of Cardioangiology, Kitasato University School of Medicine,
Sagamihara City, Kanagawa, Japan.
(8)Institute for Clinical Research, Osaka National Hospital, Osaka, Japan.
(9)Bayer Yakuhin Ltd, Osaka, Japan.
(10)Bayer Yakuhin Ltd, Osaka, Japan. Electronic address:
hori-ma@mc.pref.osaka.jp.
BACKGROUND: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese
patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was
noninferior to warfarin with respect to the principal safety outcome. In this
subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin
in relation to patients' CHADS2 scores.
RESULTS: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and
4. No statistically significant interactions were observed between principal
safety outcome event rates and CHADS2 scores with respect to treatment groups (P
value for interaction = .700). Irrespective of stratification into moderate- and
high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no
differences in principal safety outcome event rates were observed between
rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio
[HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11;
95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end
point rate in the rivaroxaban-treated group was numerically lower than in the
warfarin-treated group, regardless of risk group stratification (moderate-risk
group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P
value for interaction = .935).
CONCLUSION: This subanalysis indicated that the safety and efficacy of
rivaroxaban compared with warfarin were similar, regardless of CHADS2 score.
Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.jstrokecerebrovasdis.2013.07.021
PMID: 23954611 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9150929
|
1. Electrophoresis. 1997 Mar-Apr;18(3-4):491-7. doi: 10.1002/elps.1150180325.
The Dictyostelium discoideum proteome--the SWISS-2DPAGE database of the
multicellular aggregate (slug).
Yan JX(1), Tonella L, Sanchez JC, Wilkins MR, Packer NH, Gooley AA, Hochstrasser
DF, Williams KL.
Author information:
(1)Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW,
Australia.
The cellular slime mold Dictyostelium discoideum is a eukaryotic microorganism
which has developmental life stages attractive to the cell and molecular
biologist. By displaying the two-dimensional polyacrylamide gel electrophoresis
(2-D PAGE) protein map of different developmental stages, the key molecules can
be identified and characterised, allowing a detailed understanding of the D.
discoideum proteome. Here we describe the preparation of reference gel of the D.
discoideum multicellular aggregate, the slug. Proteins were separated by 2-D
PAGE with immobilised pH gradients (pH 3.5-10) in the first dimension and sodium
dodecyl sulfate (SDS)-PAGE in the second dimension. Micropreparative gels were
electroblotted onto polyvinylidene difluoride (PVDF) membranes and 150 spots
were visualised by amido black staining. Protein spots were excised and 31 were
putatively identified by matching their amino acid composition, estimated
isoelectric point (pI) and molecular weight (M(r)) against the SWISS-PROT
database with the ExPASy AAcompID tool (http://
expasy.hcuge.ch/ch2d/aacompi.html). A total of 25 proteins were identified by
matching against database entries for D. discoideum, and another six by
cross-species matching against database entries for Saccharomyces cerevisiae
proteins. This map will be available in the SWISS-2DPAGE database.
DOI: 10.1002/elps.1150180325
PMID: 9150929 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23391196
|
1. J Am Coll Cardiol. 2013 Feb 12;61(6):651-8. doi: 10.1016/j.jacc.2012.09.057.
Outcomes of discontinuing rivaroxaban compared with warfarin in patients with
nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban
Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism
for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Patel MR(1), Hellkamp AS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, Singer
DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Becker RC, Nessel CC,
Berkowitz SD, Califf RM, Fox KA, Mahaffey KW.
Author information:
(1)Duke Clinical Research Institute, Duke University Medical Center, Durham,
North Carolina, USA. manesh.patel@duke.edu
Comment in
J Am Coll Cardiol. 2013 Feb 12;61(6):659-60. doi:
10.1016/j.jacc.2012.09.056.
OBJECTIVES: The purpose of this study was to understand the possible risk of
discontinuation in the context of clinical care.
BACKGROUND: Rivaroxaban is noninferior to warfarin for preventing stroke in
atrial fibrillation patients. Concerns exist regarding possible increased risk
of stroke and non-central nervous system (CNS) thromboembolic events early after
discontinuation of rivaroxaban.
METHODS: We undertook a post-hoc analysis of data from the ROCKET AF
(Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin
K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation,
n = 14,624) for stroke or non-CNS embolism within 30 days after temporary
interruptions of 3 days or more, early permanent study drug discontinuation, and
end-of-study transition to open-label therapy.
RESULTS: Stroke and non-CNS embolism occurred at similar rates after temporary
interruptions (rivaroxaban: n = 9, warfarin: n = 8, 6.20 vs. 5.05/100
patient-years, hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 0.49 to
3.31, p = 0.62) and after early permanent discontinuation (rivaroxaban: n = 42,
warfarin: n = 36, 25.60 vs. 23.28/100 patient-years, HR: 1.10, 95% CI: 0.71 to
1.72, p = 0.66). Patients transitioning to open-label therapy at the end of the
study had more strokes with rivaroxaban (n = 22) versus warfarin (n = 6, 6.42
vs. 1.73/100 patient-years, HR: 3.72, 95% CI: 1.51 to 9.16, p = 0.0044) and took
longer to reach a therapeutic international normalized ratio with rivaroxaban
versus warfarin. All thrombotic events within 30 days of any study drug
cessation (including stroke, non-CNS embolism, myocardial infarction, and
vascular death) were similar between groups (HR: 1.02, 95% CI: 0.83 to 1.26, p =
0.85).
CONCLUSIONS: In atrial fibrillation patients who temporarily or permanently
discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar
with rivaroxaban or warfarin. An increased risk of stroke and non-CNS embolism
was observed in rivaroxaban-treated patients compared with warfarin-treated
patients after the end of the study, underscoring the importance of therapeutic
anticoagulation coverage during such a transition.
Copyright © 2013 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2012.09.057
PMID: 23391196 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15827065
|
1. Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E419-28. doi:
10.1152/ajpendo.00512.2004. Epub 2005 Apr 12.
Proteomic analysis on insulin signaling in human hematopoietic cells:
identification of CLIC1 and SRp20 as novel downstream effectors of insulin.
Saeki K(1), Yasugi E, Okuma E, Breit SN, Nakamura M, Toda T, Kaburagi Y, Yuo A.
Author information:
(1)Department of Hematology, Research Institute, International Medical Center of
Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Insulin/IGF-I-dependent signals play important roles for the regulation of
proliferation, differentiation, metabolism, and autophagy in various cells,
including hematopoietic cells. Although the early protein kinase activation
cascade has been intensively studied, the whole picture of intracellular
signaling events has not yet been clarified. To identify novel downstream
effectors of insulin-dependent signals in relatively early phases, we performed
high-resolution two-dimensional electrophoresis (2-DE)-based proteomic analysis
using human hematopoietic cells 1 h after insulin stimulation. We identified
SRp20, a splicing factor, and CLIC1, an intracellular chloride ion channel, as
novel downstream effectors besides previously reported effectors of Rho-guanine
nucleotide dissociation inhibitor 2 and glutathione S-transferase-pi. Reduction
in SRp20 was confirmed by one-dimensional Western blotting. Moreover, MG-132, a
proteasome inhibitor, prevented this reduction. By contrast, upregulation of
CLIC1 was not observed in one-dimensional Western blotting, unlike the 2-DE
results. As hydrophilic proteins were predominantly recovered in 2-DE, the
discrepancy between the 1-DE and 2-DE results may indicate a certain qualitative
change of the protein. Indeed, the nuclear localization pattern of CLIC1 was
remarkably changed by insulin stimulation. Thus insulin induces the
proteasome-dependent degradation of SRp20 as well as the subnuclear
relocalization of CLIC1.
DOI: 10.1152/ajpendo.00512.2004
PMID: 15827065 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24552831
|
1. Circulation. 2014 May 6;129(18):1850-9. doi:
10.1161/CIRCULATIONAHA.113.005754. Epub 2014 Feb 19.
Outcomes of temporary interruption of rivaroxaban compared with warfarin in
patients with nonvalvular atrial fibrillation: results from the rivaroxaban once
daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for
prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).
Sherwood MW(1), Douketis JD, Patel MR, Piccini JP, Hellkamp AS, Lokhnygina Y,
Spyropoulos AC, Hankey GJ, Singer DE, Nessel CC, Mahaffey KW, Fox KA, Califf RM,
Becker RC; ROCKET AF Investigators.
Author information:
(1)Division of Cardiovascular Medicine, Duke University Medical Center, Duke
Clinical Research Institute, Durham, NC (M.W.S., M.R.P., J.P.P., A.S.H., Y.L.,
R.M.C., R.C.B.); Department of Medicine, Division of Hematology and
Thromboembolism, McMaster University, Hamilton, Ontario, Canada (J.D.D.);
Department of Medicine, Division of Hematology, Hofstra North Shore/LIJ School
of Medicine, Lenox Hill Hospital, New York, NY (A.C.S.); School of Medicine and
Pharmacology, University of Western Australia, Perth, Western Australia,
Australia (G.J.H.); Department of Medicine, Massachusetts General Hospital and
Harvard Medical School, Boston, MA (D.E.S.); Johnson & Johnson Pharmaceutical
Research and Development, Raritan, NJ (C.C.N.); Department of Medicine, Stanford
University Medical Center, Palo Alto, CA (K.W.M.); and Department of Medicine,
University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United
Kingdom (K.A.A.F.).
BACKGROUND: During long-term anticoagulation in atrial fibrillation, temporary
interruptions (TIs) of therapy are common, but the relationship between patient
outcomes and TIs has not been well studied. We sought to determine reasons for
TI, the characteristics of patients undergoing TI, and the relationship between
anticoagulant and outcomes among patients with TI.
METHODS AND RESULTS: In the Rivaroxaban Once Daily, Oral, Direct Factor Xa
Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind,
double-dummy study of rivaroxaban and warfarin in nonvalvular atrial
fibrillation, baseline characteristics, management, and outcomes, including
stroke, non-central nervous system systemic embolism, death, myocardial
infarction, and bleeding, were reported in participants who experienced TI (3-30
days) for any reason. The at-risk period for outcomes associated with TI was
from TI start to 30 days after resumption of study drug. In 14 236 participants
who received at least 1 dose of study drug, 4692 (33%) experienced TI.
Participants with TI were similar to the overall ROCKET AF population in regard
to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved
bridging therapy. Stroke/systemic embolism rates during the at-risk period were
similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus
0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40).
Risk of major bleeding during the at-risk period was also similar in
rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30
days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).
CONCLUSIONS: TI of oral anticoagulation is common and is associated with
substantial stroke risks and bleeding risks that were similar among patients
treated with rivaroxaban or warfarin. Further investigation is needed to
determine the optimal management strategy in patients with atrial fibrillation
requiring TI of anticoagulation.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique
identifier: NCT00403767.
DOI: 10.1161/CIRCULATIONAHA.113.005754
PMCID: PMC4206548
PMID: 24552831 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25083135
|
1. Vasc Health Risk Manag. 2014 Jul 17;10:425-34. doi: 10.2147/VHRM.S63298.
eCollection 2014.
XANTUS: rationale and design of a noninterventional study of rivaroxaban for the
prevention of stroke in patients with atrial fibrillation.
Camm AJ(1), Amarenco P(2), Haas S(3), Hess S(4), Kirchhof P(5), van Eickels
M(4), Turpie AG(6).
Author information:
(1)Division of Clinical Sciences, St George's, University of London, London, UK.
(2)Department of Neurology and Stroke Center, Paris-Diderot-Sorbonne University,
Paris, France.
(3)Vascular Center, Munich, Germany.
(4)Medical Affairs, Bayer HealthCare Pharmaceuticals, Berlin, Germany.
(5)Centre for Cardiovascular Sciences, University of Birmingham and Sandwell &
West Birmingham Hospitals NHS Trust, Birmingham, UK ; Department of
Cardiovascular Medicine, University of Münster, Münster, Germany.
(6)Department of Medicine, McMaster University, Hamilton, ON, Canada.
Atrial fibrillation (AF) is associated with a fivefold increase in the risk of
stroke. The Phase III ROCKET AF (Rivaroxaban Once-Daily Oral Direct Factor Xa
Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation) trial showed that rivaroxaban, an oral,
direct Factor Xa inhibitor, was noninferior to warfarin for the reduction of
stroke or systemic embolism in patients with AF. Compared with warfarin,
rivaroxaban significantly reduced rates of intracranial and fatal hemorrhages,
although not rates of bleeding overall. XANTUS (Xarelto(®) for Prevention of
Stroke in Patients with Atrial Fibrillation) is a prospective, international,
observational, postauthorization, noninterventional study designed to collect
safety and efficacy data on the use of rivaroxaban for stroke prevention in AF
in routine clinical practice. The key goal is to determine whether the safety
profile of rivaroxaban established in ROCKET AF is also observed in routine
clinical practice. XANTUS is designed as a single-arm cohort study to minimize
selection bias, and will enroll approximately 6,000 patients (mostly from
Europe) with nonvalvular AF prescribed rivaroxaban, irrespective of their level
of stroke risk. Overall duration of follow-up will be 1 year; the first patient
was enrolled in June 2012. Similar studies (XANTUS-EL [Xarelto(®) for Prevention
of Stroke in Patients with Nonvalvular Atrial Fibrillation, Eastern Europe,
Middle East, Africa and Latin America] and XANAP [Xarelto(®) for Prevention of
Stroke in Patients with Atrial Fibrillation in Asia-Pacific]) are ongoing in
Latin America and Asia-Pacific. Data from these studies will supplement those
from ROCKET AF and provide practical information concerning the use of
rivaroxaban for stroke prevention in AF.
DOI: 10.2147/VHRM.S63298
PMCID: PMC4108256
PMID: 25083135 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25148838
|
1. Eur Heart J. 2014 Dec 14;35(47):3377-85. doi: 10.1093/eurheartj/ehu305. Epub
2014 Aug 22.
Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients
with non-valvular atrial fibrillation but underlying native mitral and aortic
valve disease participating in the ROCKET AF trial.
Breithardt G(1), Baumgartner H(2), Berkowitz SD(3), Hellkamp AS(4), Piccini
JP(4), Stevens SR(4), Lokhnygina Y(4), Patel MR(4), Halperin JL(5), Singer
DE(6), Hankey GJ(7), Hacke W(8), Becker RC(4), Nessel CC(9), Mahaffey KW(10),
Fox KA(11), Califf RM(12); ROCKET AF Steering Committee & Investigators.
Author information:
(1)Department of Cardiovascular Medicine, Division of Electrophysiology,
University Hospital Münster, Von-Esmarch-Strasse 117, Münster D-48149, Germany
g.breithardt@uni-muenster.de.
(2)Department of Cardiovascular Medicine, Division of Adult Congenital and
Valvular Heart Disease, University Hospital Münster, Münster, Germany.
(3)Bayer Healthcare Pharmaceuticals, L.P., Whippany, NJ, USA.
(4)Duke Clinical Research Institute, Duke University Medical Center, Durham, NC,
USA.
(5)The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY, USA.
(6)Clinical Epidemiology Unit, General Medicine Division, Massachusetts General
Hospital, and Harvard Medical School, Boston, MA, USA.
(7)School of Medicine and Pharmacology, The University of Western Australia,
Perth, Australia.
(8)Ruprecht-Karls-University, Heidelberg, Germany.
(9)Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA.
(10)Department of Medicine, Stanford University, Stanford, CA, USA.
(11)University of Edinburgh, and Royal Infirmary of Edinburgh, Edinburgh, UK.
(12)Duke Translational Medicine Institute, Duke University Medical Center,
Durham, NC, USA.
Comment in
Eur Heart J. 2014 Dec 14;35(47):3323-5. doi: 10.1093/eurheartj/ehu386.
AIMS: We investigated clinical characteristics and outcomes of patients with
significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct
Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.
METHODS AND RESULTS: ROCKET AF excluded patients with mitral stenosis or
artificial valve prostheses. We used Cox regression to adjust comparisons for
potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were
older and had more comorbidities than patients without SVD. The rate of stroke
or systemic embolism with rivaroxaban vs. warfarin was consistent among patients
with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI)
0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07;
interaction P = 0.76). However, rates of major and non-major clinically relevant
bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8%
rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without
(14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P
= 0.034), even when controlling for risk factors and potential confounders. In
intracranial haemorrhage, there was no interaction between patients with and
without SVD where the overall rate was lower among those randomized to
rivaroxaban.
CONCLUSIONS: Many patients with 'non-valvular atrial fibrillation' have
significant valve lesions. Their risk of stroke is similar to that of patients
without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban
vs. warfarin was similar in patients with and without SVD; however, the observed
risk of bleeding was higher with rivaroxaban in patients with SVD but was the
same among those without SVD. Atrial fibrillation patients with and without SVD
experience the same stroke-preventive benefit of oral anticoagulants.
© The Author 2014. Published by Oxford University Press on behalf of the
European Society of Cardiology.
DOI: 10.1093/eurheartj/ehu305
PMCID: PMC4265383
PMID: 25148838 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18202123
|
1. Endocrinology. 2008 Mar;149(3):942-9. doi: 10.1210/en.2007-1713. Epub 2008 Jan
17.
Lipid droplets in lipogenesis and lipolysis.
Ducharme NA(1), Bickel PE.
Author information:
(1)Center for Diabetes and Obesity Research, Brown Foundation Institute of
Molecular Medicine, 1825 Pressler Street, University of Texas Health Science
Center at Houston, Houston, Texas 77030, USA.
Organisms store energy for later use during times of nutrient scarcity. Excess
energy is stored as triacylglycerol in lipid droplets during lipogenesis. When
energy is required, the stored triacylglycerol is hydrolyzed via activation of
lipolytic pathways. The coordination of lipid storage and utilization is
regulated by the perilipin family of lipid droplet coat proteins [perilipin,
adipophilin/adipocyte differentiation-related protein (ADRP), S3-12,
tail-interacting protein of 47 kilodaltons (TIP47), and myocardial lipid droplet
protein (MLDP)/oxidative tissues-enriched PAT protein (OXPAT)/lipid storage
droplet protein 5 (LSDP5)]. Lipid droplets are dynamic and heterogeneous in
size, location, and protein content. The proteins that coat lipid droplets
change during lipid droplet biogenesis and are dependent upon multiple factors,
including tissue-specific expression and metabolic state (basal vs. lipogenic
vs. lipolytic). New data suggest that proteins previously implicated in vesicle
trafficking, including Rabs, soluble N-ethylmaleimide sensitive factor
attachment protein receptors (SNAREs), and motor and cytoskeletal proteins,
likely orchestrate the movement and fusion of lipid droplets. Thus, rather than
inert cytoplasmic inclusions, lipid droplets are now appreciated as dynamic
organelles that are critical for management of cellular lipid stores. That much
remains to be discovered is suggested by the recent identification of a novel
lipase [adipocyte triglyceride lipase (ATGL)] and lipase regulator [Comparative
Gene Identification-58 (CGI-58)], which has led to reconsideration of the
decades-old model of lipolysis. Future discovery likely will be driven by the
exploitation of model organisms and by human genetic studies.
DOI: 10.1210/en.2007-1713
PMID: 18202123 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16980188
|
1. Stud Hist Philos Biol Biomed Sci. 2006 Sep;37(3):459-83. doi:
10.1016/j.shpsc.2006.06.010. Epub 2006 Aug 24.
'Your true and proper gender': the Barr body as a good enough science of sex.
Miller FA(1).
Author information:
(1)Department of Clinical Epidemiology & Biostatistics, Centre for Health
Economics and Policy Analysis, McMaster University, Health Science Centre 3H1A,
1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. millerf@mcmaster.ca
In the late 1940s, a microanatomist from London Ontario, Murray Barr, discovered
a mark of sex chromosome status in bodily tissues, what came to be known as the
'Barr body'. This discovery offered an important diagnostic technology to the
burgeoning clinical science community engaged with the medical interpretation
and management of sexual anomalies. It seemed to offer a way to identify the
true, underlying sex in those whose bodies or lives were sexually anomalous
(intersexuals, homosexuals and transsexuals). The hypothesis that allowed the
Barr body to stand in for 'chromosomal' or 'genetic' sex was provisional, but it
supported the expectation that genetic information established one's primary
identity, and the conviction that the animal world could be neatly divided into
two, and only two, sexes. Ultimately, this provisional hypothesis, and its
status as an unambiguous arbiter of true sex, was overturned. But during much of
the 1950s, Barr's thesis about the identity of the Barr body was consistent with
a coherent set of theories and evidence explaining sexual development and sexual
pathology. Though provisional, the scientific status of the sex chromatin within
this system of knowledge was good enough to support a flourishing research
enterprise in the clinical sciences.
DOI: 10.1016/j.shpsc.2006.06.010
PMID: 16980188 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23405833
|
1. Expert Rev Cardiovasc Ther. 2013 Feb;11(2):129-41. doi: 10.1586/erc.12.172.
Rivaroxaban: a once-daily anticoagulant for the prevention of thromboembolic
complications.
Barrios V(1), Escobar C.
Author information:
(1)Department of Cardiology, Hospital Universitario Ramón y Cajal, Madrid,
Spain. vbarrios.hrc@salud.madrid.org
The majority of patients with nonvalvular atrial fibrillation (AF) will require
anticoagulation therapy for reducing the risk of stroke, the most devastating
complication of AF. Although traditionally vitamin K antagonists have been used
for this purpose, they have important limitations that interfere with their use
in clinical practice. Different clinical trials have shown the benefits of new
oral anticoagulants over warfarin, but patients included in the ROCKET-AF trial
were found to be at a higher risk of AF-related complications. Moreover,
rivaroxaban has been proven to be effective and safe in patients with AF and
moderate renal dysfunction as well as in those with ischemic heart disease.
Rivaroxaban is taken only once daily; this may improve medication adherence and,
secondarily, it provides a higher protection and reduction in the risk of
stroke. This article provides an extensive review of the available evidence
about rivaroxaban, with a special focus on nonvalvular AF.
DOI: 10.1586/erc.12.172
PMID: 23405833 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25209598
|
1. Eur Heart J. 2015 Feb 1;36(5):288-96. doi: 10.1093/eurheartj/ehu359. Epub 2014
Sep 10.
Higher risk of death and stroke in patients with persistent vs. paroxysmal
atrial fibrillation: results from the ROCKET-AF Trial.
Steinberg BA(1), Hellkamp AS(2), Lokhnygina Y(2), Patel MR(2), Breithardt G(3),
Hankey GJ(4), Becker RC(5), Singer DE(6), Halperin JL(7), Hacke W(8), Nessel
CC(9), Berkowitz SD(10), Mahaffey KW(11), Fox KA(12), Califf RM(13), Piccini
JP(2); ROCKET-AF Steering Committee and Investigators.
Author information:
(1)Duke Clinical Research Institute, PO Box 17969, NC 27715 Durham, NC, USA
benjamin.steinberg@duke.edu.
(2)Duke Clinical Research Institute, PO Box 17969, NC 27715 Durham, NC, USA.
(3)Department of Cardiovascular Medicine, Hospital of the University of Münster,
Münster, Germany.
(4)School of Medicine and Pharmacology, The University of Western Australia,
Crawley, Australia.
(5)University of Cincinnati College of Medicine, Cincinnati, OH, USA.
(6)Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
(7)Mount Sinai Medical Center, Cardiovascular Institute, New York, NY, USA.
(8)Ruprecht-Karls-University, Heidelberg, Germany.
(9)Janssen Research & Development LLC, Raritan, NJ, USA.
(10)Bayer HealthCare Pharmaceuticals, Montville, NJ, USA.
(11)Stanford University School of Medicine, Stanford, CA, USA.
(12)University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, UK.
(13)Duke University Medical Center, Duke Translational Medicine Institute,
Durham, NC, USA.
AIM: Anticoagulation prophylaxis for stroke is recommended for at-risk patients
with either persistent or paroxysmal atrial fibrillation (AF). We compared
outcomes in patients with persistent vs. paroxysmal AF receiving oral
anticoagulation.
METHODS AND RESULTS: Patients randomized in the Rivaroxaban Once Daily Oral
Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264)
were grouped by baseline AF category: paroxysmal or persistent. Multivariable
adjustment was performed to compare thrombo-embolic events, bleeding, and death
between groups, in high-risk subgroups, and across treatment assignment
(rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF
and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally
older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and
more likely to have previously used vitamin K antagonists (64 vs. 56%, P <
0.0001) compared with patients with paroxysmal AF. In patients randomized to
warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients
with persistent AF had higher adjusted rates of stroke or systemic embolism
(2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality
(4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31,
P = 0.77). Rates of stroke or systemic embolism in both types of AF did not
differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6).
CONCLUSION: In patients with AF at moderate-to-high risk of stroke receiving
anticoagulation, those with persistent AF have a higher risk of thrombo-embolic
events and worse survival compared with paroxysmal AF.
© The Author 2014. Published by Oxford University Press on behalf of the
European Society of Cardiology.
DOI: 10.1093/eurheartj/ehu359
PMCID: PMC4313363
PMID: 25209598 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8978813
|
1. J Cell Biol. 1996 Dec;135(6 Pt 1):1427-40. doi: 10.1083/jcb.135.6.1427.
Three-dimensional reconstruction of painted human interphase chromosomes: active
and inactive X chromosome territories have similar volumes but differ in shape
and surface structure.
Eils R(1), Dietzel S, Bertin E, Schröck E, Speicher MR, Ried T, Robert-Nicoud M,
Cremer C, Cremer T.
Author information:
(1)Interdisciplinary Center of Scientific Computing (IWR), University of
Heidelberg, Germany.
This study provides a three-dimensional (3D) analysis of differences between the
3D morphology of active and inactive human X interphase chromosomes (Xa and Xi
territories). Chromosome territories were painted in formaldehyde-fixed,
three-dimensionally intact human diploid female amniotic fluid cell nuclei (46,
XX) with X-specific whole chromosome compositive probes. The colocalization of a
4,6-diamidino-2-phenylindole dihydrochloride-stained Barr body with one of the
two painted X territories allowed the unequivocal discrimination of the inactive
X from its active counterpart. Light optical serial sections were obtained with
a confocal laser scanning microscope. 3D-reconstructed Xa territories revealed a
flatter shape and exhibited a larger and more irregular surface when compared to
the apparently smoother surface and rounder shape of Xi territories. The
relationship between territory surface and volume was quantified by the
determination of a dimensionless roundness factor (RF). RF and surface area
measurements showed a highly significant difference between Xa and Xi
territories (P < 0.001) in contrast to volume differences (P > 0.1). For
comparison with an autosome of similar DNA content, chromosome 7 territories
were additionally painted. The 3D morphology of the chromosome 7 territories was
similar to the Xa territory but differed strongly from the Xi territory with
respect to RF and surface area (P < 0.001).
DOI: 10.1083/jcb.135.6.1427
PMCID: PMC2133958
PMID: 8978813 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24763930
|
1. Stroke. 2014 Jun;45(6):1739-47. doi: 10.1161/STROKEAHA.113.002968. Epub 2014
Apr 24.
Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF
trial.
Wong KS(1), Hu DY(2), Oomman A(2), Tan RS(2), Patel MR(2), Singer DE(2),
Breithardt G(2), Mahaffey KW(2), Becker RC(2), Califf R(2), Fox KA(2), Berkowitz
SD(2), Hacke W(2), Hankey GJ(2); Executive Steering Committee and the ROCKET AF
Study Investigators.
Author information:
(1)From the Department of Medicine and Therapeutics, Chinese University of Hong
Kong, Prince of Wales Hospital, Hong Kong, China (K.S.L.W.); Heart Center,
Peking University People's Hospital, Beijing, China (D.Y.H.); Department of
Cardiology, Apollo Hospital, Chennai, India (A.O.); National Heart Centre,
Singapore, Singapore (R.-S.T.); Department of Medicine, Division of Cardiology,
Duke Clinical Research Institute (M.R.P., K.W.M., R.C.B.) and Department of
Medicine, Division of Cardiology, Duke Translational Medicine Institute (R.C.),
Duke University Medical Center, Durham, NC; Department of Epidemiology,
Massachusetts General Hospital and Harvard Medical School, Boston (D.E.S.);
Department of Cardiovascular Medicine, University Hospital Münster, Münster,
Germany (G.B.); Centre for Cardiovascular Science, University of Edinburgh and
Royal Infirmary of Edinburgh, Edinburgh, Scotland (K.A.A.F.); Bayer HealthCare
Pharmaceuticals, Montville, NJ (S.D.B.); Department of Neurology,
Ruprecht-Karls-University, Heidelberg, Germany (W.H.); and Stroke Unit,
Department of Neurology, Royal Perth Hospital, University of Western Australia,
Perth, Australia (G.J.H.). ks-wong@cuhk.edu.hk.
(2)From the Department of Medicine and Therapeutics, Chinese University of Hong
Kong, Prince of Wales Hospital, Hong Kong, China (K.S.L.W.); Heart Center,
Peking University People's Hospital, Beijing, China (D.Y.H.); Department of
Cardiology, Apollo Hospital, Chennai, India (A.O.); National Heart Centre,
Singapore, Singapore (R.-S.T.); Department of Medicine, Division of Cardiology,
Duke Clinical Research Institute (M.R.P., K.W.M., R.C.B.) and Department of
Medicine, Division of Cardiology, Duke Translational Medicine Institute (R.C.),
Duke University Medical Center, Durham, NC; Department of Epidemiology,
Massachusetts General Hospital and Harvard Medical School, Boston (D.E.S.);
Department of Cardiovascular Medicine, University Hospital Münster, Münster,
Germany (G.B.); Centre for Cardiovascular Science, University of Edinburgh and
Royal Infirmary of Edinburgh, Edinburgh, Scotland (K.A.A.F.); Bayer HealthCare
Pharmaceuticals, Montville, NJ (S.D.B.); Department of Neurology,
Ruprecht-Karls-University, Heidelberg, Germany (W.H.); and Stroke Unit,
Department of Neurology, Royal Perth Hospital, University of Western Australia,
Perth, Australia (G.J.H.).
Comment in
Stroke. 2014 Jun;45(6):1608-9. doi: 10.1161/STROKEAHA.114.005339.
BACKGROUND AND PURPOSE: In Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was
noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism
among patients with nonvalvular atrial fibrillation at moderate to high stroke
risk. Because of differences in patient demographics, epidemiology, and stroke
risk management in East Asia, outcomes and relative effects of rivaroxaban
versus warfarin were assessed to determine consistency among East Asians versus
other ROCKET AF participants.
METHODS: Baseline demographics and interaction of treatment effects of
rivaroxaban and warfarin among patients within East Asia and outside were
assessed.
RESULTS: A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At
baseline, East Asians had lower weight, creatinine clearance, and prior vitamin
K antagonist use; higher prevalence of prior stroke; and less congestive heart
failure and prior myocardial infarction than other participants. Despite higher
absolute event rates for efficacy and safety outcomes in East Asians, the
relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for
creatinine clearance of 30-49 mL/min) versus warfarin with respect to the
primary efficacy end point (stroke/systemic embolism) was consistent among East
Asians and non-East Asians (interaction P=0.666). Relative event rates for the
major or nonmajor clinically relevant bleeding in patients treated with
rivaroxaban and warfarin were consistent among East Asians and non-East Asians
(interaction P=0.867).
CONCLUSIONS: Observed relative efficacy and safety of rivaroxaban versus
warfarin were similar among patients within and outside East Asia. Rivaroxaban,
20 mg once daily, is an alternative to warfarin for stroke prevention in East
Asians with nonvalvular atrial fibrillation.
© 2014 American Heart Association, Inc.
DOI: 10.1161/STROKEAHA.113.002968
PMID: 24763930 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24315894
|
1. J Am Coll Cardiol. 2014 Mar 11;63(9):891-900. doi: 10.1016/j.jacc.2013.11.013.
Epub 2013 Dec 4.
Factors associated with major bleeding events: insights from the ROCKET AF trial
(rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K
antagonism for prevention of stroke and embolism trial in atrial fibrillation).
Goodman SG(1), Wojdyla DM(2), Piccini JP(2), White HD(3), Paolini JF(4), Nessel
CC(5), Berkowitz SD(4), Mahaffey KW(2), Patel MR(2), Sherwood MW(2), Becker
RC(2), Halperin JL(6), Hacke W(7), Singer DE(8), Hankey GJ(9), Breithardt G(10),
Fox KA(11), Califf RM(12); ROCKET AF Investigators.
Author information:
(1)Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division
of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario,
Canada. Electronic address: goodmans@chrc.net.
(2)Duke Clinical Research Institute, Duke University Medical Center, Durham,
North Carolina.
(3)Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New
Zealand.
(4)Bayer HealthCare Pharmaceuticals, Montville, New Jersey.
(5)Janssen Research and Development, Raritan, New Jersey.
(6)Cardiovascular Institute, Mount Sinai Medical Center, New York, New York.
(7)Ruprecht-Karls-University, Heidelberg, Germany.
(8)Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts.
(9)Royal Perth Hospital, Perth, Australia.
(10)Hospital of the University of Münster, Münster, Germany.
(11)University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh,
Scotland, United Kingdom.
(12)Duke Clinical Research Institute and Duke Translational Medicine Institute,
Duke University Medical Center, Durham, North Carolina.
OBJECTIVES: This study sought to report additional safety results from the
ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial
Fibrillation).
BACKGROUND: The ROCKET AF trial demonstrated similar risks of stroke/systemic
embolism and major/nonmajor clinically relevant bleeding (principal safety
endpoint) with rivaroxaban and warfarin.
METHODS: The risk of the principal safety and component bleeding endpoints with
rivaroxaban versus warfarin were compared, and factors associated with major
bleeding were examined in a multivariable model.
RESULTS: The principal safety endpoint was similar in the rivaroxaban and
warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95%
confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but
there were no differences between treatments in each age category (<65, 65 to
74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455),
patients with a major bleed (n = 781) were more likely to be older,
current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia,
and a lower calculated creatinine clearance and less likely to be female or have
a prior stroke/transient ischemic attack. Increasing age, baseline diastolic
blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease
or GI bleeding, prior acetylsalicylic acid use, and anemia were independently
associated with major bleeding risk; female sex and DBP <90 mm Hg were
associated with a decreased risk.
CONCLUSIONS: Rivaroxaban and warfarin had similar risk for major/nonmajor
clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior
acetylsalicylic acid use, and anemia were associated with the risk of major
bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the
Prevention of Stroke and Non-Central Nervous System Systemic Embolism in
Patients With Non-Valvular Atrial Fibrillation: NCT00403767).
Copyright © 2014 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2013.11.013
PMCID: PMC4206565
PMID: 24315894 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19717842
|
1. J Biol Chem. 2009 Nov 13;284(46):32116-25. doi: 10.1074/jbc.M109.006726. Epub
2009 Aug 29.
Activation of hormone-sensitive lipase requires two steps, protein
phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins.
Wang H(1), Hu L, Dalen K, Dorward H, Marcinkiewicz A, Russell D, Gong D, Londos
C, Yamaguchi T, Holm C, Rizzo MA, Brasaemle D, Sztalryd C.
Author information:
(1)Geriatric Research, Education, and Clinical Center, Baltimore Veterans
Affairs Health Care Center, University of Maryland School of Medicine,
Baltimore, Maryland 21201, USA.
Lipolysis is an important metabolic pathway controlling energy homeostasis
through degradation of triglycerides stored in lipid droplets and release of
fatty acids. Lipid droplets of mammalian cells are coated with one or more
members of the PAT protein family, which serve important functions in regulating
lipolysis. In this study, we investigate the mechanisms by which PAT family
members, perilipin A, adipose differentiation-related protein (ADFP), and LSDP5,
control lipolysis catalyzed by hormone-sensitive lipase (HSL), a major lipase in
adipocytes and several non-adipose cells. We applied fluorescence microscopic
tools to analyze proteins in situ in cultured Chinese hamster ovary cells using
fluorescence recovery after photobleaching and anisotropy Forster resonance
energy transfer. Fluorescence recovery after photobleaching data show that ADFP
and LSDP5 exchange between lipid droplet and cytoplasmic pools, whereas
perilipin A does not. Differences in protein mobility do not correlate with PAT
protein-mediated control of lipolysis catalyzed by HSL or endogenous lipases.
Forster resonance energy transfer and co-immunoprecipitation experiments reveal
that each of the three PAT proteins bind HSL through interaction of the lipase
with amino acids within the highly conserved amino-terminal PAT-1 domain. ADFP
and LSDP5 bind HSL under basal conditions, whereas phosphorylation of serine
residues within three amino-terminal protein kinase A consensus sequences of
perilipin A is required for HSL binding and maximal lipolysis. Finally, protein
kinase A-mediated phosphorylation of HSL increases lipolysis in cells expressing
ADFP or LSDP5; in contrast, phosphorylation of perilipin A exerts the major
control over HSL-mediated lipolysis when perilipin is the main lipid droplet
protein.
DOI: 10.1074/jbc.M109.006726
PMCID: PMC2797282
PMID: 19717842 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21420243
|
1. Meat Sci. 2011 Aug;88(4):631-7. doi: 10.1016/j.meatsci.2011.02.020. Epub 2011
Feb 24.
Perilipin 1 and perilipin 2 protein localization and gene expression study in
skeletal muscles of European cross-breed pigs with different intramuscular fat
contents.
Gandolfi G(1), Mazzoni M, Zambonelli P, Lalatta-Costerbosa G, Tronca A, Russo V,
Davoli R.
Author information:
(1)Department of Agri-food Protection and Valorization (DIPROVAL), Faculty of
Agriculture, University of Bologna, Reggio Emilia, Italy.
greta.gandolfi2@unibo.it
This study investigated the lipid droplet coat proteins perilipin 1 (PLIN1) and
perilipin 2 (PLIN2) localization in pig skeletal muscle and their relationship
with intramuscular fat (IMF) content. PLIN1 and PLIN2 proteins were
immunostained in semimembranosus muscle cross-sections from two groups of
samples divergent for IMF and the gene expression was quantified. PLIN1
localized in the periphery of intramuscular adipocytes, whereas PLIN2 localized
within myofibers with high lipid content. The high IMF group showed higher total
cross-sectional area of PLIN1-stained adipocytes compared with the low IMF group
(P<0.05), while the cross-sectional area and percentage of PLIN2-positive
myofibers did not differ between IMF-divergent groups. This suggested that IMF
content is mainly determined by extra-myocellular lipids. At mRNA level, PLIN2
expression was higher in high IMF muscles (P<0.05). The results indicate for the
first time that in pig muscle PLIN1 and PLIN2 proteins are localized in
correspondence with extra and intra-myocellular lipids, respectively.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.meatsci.2011.02.020
PMID: 21420243 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23204327
|
1. Mol Endocrinol. 2013 Jan;27(1):116-26. doi: 10.1210/me.2012-1178. Epub 2012
Nov 30.
Distinct mechanisms regulate ATGL-mediated adipocyte lipolysis by lipid droplet
coat proteins.
Yang X(1), Heckmann BL, Zhang X, Smas CM, Liu J.
Author information:
(1)Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona,
Scottsdale, Arizona 85259, USA.
Adipose triglyceride lipase (ATGL) is the key triacylglycerol hydrolase in
adipocytes. The precise mechanisms by which ATGL action is regulated by lipid
droplet (LD) coat proteins and responds to hormonal stimulation are incompletely
defined. By combining usage of loss- and gain-of-function approaches, we sought
to determine the respective roles of perilipin 1 and fat-specific protein 27
(FSP27) in the control of ATGL-mediated lipolysis in adipocytes. Knockdown of
endogenous perilipin 1 expression resulted in elevated basal lipolysis that was
less responsive to β-adrenergic agonist isoproterenol. In comparison, depletion
of FSP27 protein increased both basal and stimulated lipolysis with no
significant impact on the overall response of cells to isoproterenol. In vitro
assays showed that perilipin but not FSP27 was able to inhibit the
triacylglycerol hydrolase activity of ATGL. Perilipin 1 also attenuated
dose-dependent activation of ATGL by its Coactivator Comparative Gene
identification-58. Accordingly, depletion of perilipin 1 and CGI-58 in
adipocytes inversely affected basal lipolysis specifically mediated by
overexpressed ATGL. Moreover, although depletion of perilipin 1 abolished the LD
translocation of ATGL stimulated by isoproterenol, absence of FSP27 resulted in
multilocularization of LDs along with increased LD presence of ATGL under both
basal and stimulated conditions. Interestingly, knockdown of ATGL expression
increased LD size and decreased LD number in FSP27-depeleted cells. Together,
our results demonstrate that although FSP27 acts to constitutively limit the LD
presence of ATGL, perilipin 1 plays an essential role in mediating the response
of ATGL action to β-adrenergic hormones.
DOI: 10.1210/me.2012-1178
PMCID: PMC3545209
PMID: 23204327 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19748893
|
1. J Biol Chem. 2009 Nov 6;284(45):30941-8. doi: 10.1074/jbc.M109.013995. Epub
2009 Sep 11.
Diacylglycerol enrichment of endoplasmic reticulum or lipid droplets recruits
perilipin 3/TIP47 during lipid storage and mobilization.
Skinner JR(1), Shew TM, Schwartz DM, Tzekov A, Lepus CM, Abumrad NA, Wolins NE.
Author information:
(1)Center for Human Nutrition, Washington University School of Medicine, St.
Louis, Missouri 63110, USA.
Fatty acid-induced triacylglycerol synthesis produces triacylglycerol droplets
with a protein coat that includes perilipin 3/TIP47 and perilipin 4/S3-12. This
study addresses the following two questions. Where do lipid droplets emerge, and
how are their coat proteins recruited? We show that perilipin 3- and perilipin
4-coated lipid droplets emerge along the endoplasmic reticulum (ER). Blocking
membrane trafficking with AlF(4)(-) during fatty acid-induced triacylglycerol
synthesis drove perilipin 3 to the tubular ER. Forskolin, which like AlF(4)(-)
activates adenylate cyclase, did not redistribute perilipin 3, but when added
together with AlF(4)(-) perilipin 3 was recruited to lipid droplets rather than
the ER. Thus inhibiting trafficking with AlF(4)(-) redistributed perilipin 3
differently under conditions of triacylglycerol synthesis (fatty acid addition)
versus hydrolysis (forskolin) suggesting a shared acylglycerol-mediated
mechanism. We tested whether diacylglycerol (DG), the immediate precursor of
triacylglycerol and its first hydrolytic product, affects the distribution of
perilipin 3. Stabilizing DG with the DG lipase inhibitor RHC80267 enhanced the
perilipin 3 recruited to lipid droplets and raised DG levels in this fraction.
Treating cells with a membrane-permeable DG recruited perilipin 3 to the ER.
Stabilizing DG, by blocking its hydrolysis with RHC80267 or its acylation with
triacsin C, enhanced recruitment of perilipin 3 to the ER. Expressing the ER
enzyme DGAT1, which removes DG by converting it to triacylglycerol, attenuated
perilipin 3 DG-induced ER recruitment. Membrane-permeable DG also drove
perilipin 4 and 5 onto the ER. Together the data suggest that these lipid
droplet proteins are recruited to DG-enriched membranes thereby linking lipid
coat proteins to the metabolic state of the cell.
DOI: 10.1074/jbc.M109.013995
PMCID: PMC2781494
PMID: 19748893 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16098176
|
1. Cell Prolif. 2005 Aug;38(4):171-4. doi: 10.1111/j.1365-2184.2005.00342.x.
Cytomics, the human cytome project and systems biology: top-down resolution of
the molecular biocomplexity of organisms by single cell analysis.
Valet G(1).
Author information:
(1)Max-Planck-Institut für Biochemie, Martinsried, Germany. valet@biochem.mpg.de
A large amount of structural and functional information is obtained by molecular
cell phenotype analysis of tissues, organs and organisms at the single cell
level by image or flow cytometry in combination with bioinformatic knowledge
extraction (cytomics) concerning nuclei acids, proteins and metabolites
(cellular genomics, proteomics and metabolomics) as well as cell function
parameters like intracellular pH, transmembrane potentials or ion gradients. In
addition, differential molecular cell phenotypes between diseased and healthy
cells provide molecular data patterns for (i) predictive medicine by cytomics or
for (ii) drug discovery purposes using reverse engineering of the data patterns
by biomedical cell systems biology. Molecular pathways can be explored in this
way including the detection of suitable target molecules, without detailed a
priori knowledge of specific disease mechanisms. This is useful during the
analysis of complex diseases such as infections, allergies, rheumatoid diseases,
diabetes or malignancies. The top-down approach reaching from single cell
heterogeneity in cell systems and tissues down to the molecular level seems
suitable for a human cytome project to systematically explore the molecular
biocomplexity of human organisms. The analysis of already existing data from
scientific studies or routine diagnostic procedures will be of immediate value
in clinical medicine, for example as personalized therapy by cytomics.
DOI: 10.1111/j.1365-2184.2005.00342.x
PMCID: PMC6496119
PMID: 16098176 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22498881
|
1. J Proteomics. 2012 Aug 30;75(16):5036-5051. doi: 10.1016/j.jprot.2012.03.017.
Epub 2012 Mar 29.
Mass spectrometry imaging and profiling of single cells.
Lanni EJ(1), Rubakhin SS(1), Sweedler JV(2).
Author information:
(1)Department of Chemistry and the Beckman Institute of Science and Technology,
University of Illinois, Urbana IL 61801, USA.
(2)Department of Chemistry and the Beckman Institute of Science and Technology,
University of Illinois, Urbana IL 61801, USA. Electronic address:
jsweedle@illinois.edu.
Mass spectrometry imaging and profiling of individual cells and subcellular
structures provide unique analytical capabilities for biological and biomedical
research, including determination of the biochemical heterogeneity of cellular
populations and intracellular localization of pharmaceuticals. Two mass
spectrometry technologies-secondary ion mass spectrometry (SIMS) and matrix
assisted laser desorption/ionization mass spectrometry (MALDI MS)-are most often
used in micro-bioanalytical investigations. Recent advances in ion probe
technologies have increased the dynamic range and sensitivity of analyte
detection by SIMS, allowing two- and three-dimensional localization of analytes
in a variety of cells. SIMS operating in the mass spectrometry imaging (MSI)
mode can routinely reach spatial resolutions at the submicron level; therefore,
it is frequently used in studies of the chemical composition of subcellular
structures. MALDI MS offers a large mass range and high sensitivity of analyte
detection. It has been successfully applied in a variety of single-cell and
organelle profiling studies. Innovative instrumentation such as scanning
microprobe MALDI and mass microscope spectrometers enables new subcellular MSI
measurements. Other approaches for MS-based chemical imaging and profiling
include those based on near-field laser ablation and inductively-coupled plasma
MS analysis, which offer complementary capabilities for subcellular chemical
imaging and profiling.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jprot.2012.03.017
PMCID: PMC3419297
PMID: 22498881 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare they have no conflicts of
interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/17109634
|
1. Cell Prolif. 2006 Dec;39(6):495-505. doi: 10.1111/j.1365-2184.2006.00407.x.
Cytomics - importance of multimodal analysis of cell function and proliferation
in oncology.
Tárnok A(1), Bocsi J, Brockhoff G.
Author information:
(1)Department of Paediatric Cardiology, Cardiac Centre Leipzig GmbH, University
of Leipzig, Leipzig, Germany. tarnok@medizin.uni-leipzig.de
Cancer is a highly complex and heterogeneous disease involving a succession of
genetic changes (frequently caused or accompanied by exogenous trauma), and
resulting in a molecular phenotype that in turn results in a malignant
specification. The development of malignancy has been described as a multistep
process involving self-sufficiency in growth signals, insensitivity to
antigrowth signals, evasion of apoptosis, limitless replicative potential,
sustained angiogenesis, and finally tissue invasion and metastasis. The
quantitative analysis of networking molecules within the cells might be applied
to understand native-state tissue signalling biology, complex drug actions and
dysfunctional signalling in transformed cells, that is, in cancer cells.
High-content and high-throughput single-cell analysis can lead to systems
biology and cytomics. The application of cytomics in cancer research and
diagnostics is very broad, ranging from the better understanding of the tumour
cell biology to the identification of residual tumour cells after treatment, to
drug discovery. The ultimate goal is to pinpoint in detail these processes on
the molecular, cellular and tissue level. A comprehensive knowledge of these
will require tissue analysis, which is multiplex and functional; thus, vast
amounts of data are being collected from current genomic and proteomic platforms
for integration and interpretation as well as for new varieties of updated
cytomics technology. This overview will briefly highlight the most important
aspects of this continuously developing field.
DOI: 10.1111/j.1365-2184.2006.00407.x
PMCID: PMC6496464
PMID: 17109634 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21416650
|
1. Diagn Cytopathol. 2012 Nov;40(11):964-6. doi: 10.1002/dc.21688. Epub 2011 Mar
17.
Barr body in fine needle aspiration cytology of ovarian malignancies.
Agrawal P(1), Dey P.
Author information:
(1)Department of Cytology, Post Graduate Institute of Medical Education and
Research, Chandigarh, India.
The Barr body is the inactive X chromosome in a female somatic cell. It is
readily identified as plano-convex structure of 2-3 micron in diameter on the
periphery of the nuclear membrane. The aim of this study is to evaluate the
significance of Barr body count in malignant ovarian tumors on fine needle
aspiration cytology (FNAC) smears. In this retrospective study, Barr body was
counted in FNAC smears of 20 successive malignant ovarian lesions and expressed
as percentage. Mean (±SD) Barr body score was 2.4 ± 2.58. Minimum Barr body
count was 1 and maximum was 9. The gross reduction of Barr body in ovarian
neoplasms is an interesting cytomorphologic finding.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/dc.21688
PMID: 21416650 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24036367
|
1. Biochimie. 2014 Jan;96:96-101. doi: 10.1016/j.biochi.2013.08.026. Epub 2013
Sep 13.
Perilipins: lipid droplet coat proteins adapted for tissue-specific energy
storage and utilization, and lipid cytoprotection.
Sztalryd C(1), Kimmel AR.
Author information:
(1)The Geriatric Research, Education and Clinical Center, Baltimore Veterans
Affairs Health Care Center, Baltimore, MD 21201, USA; Division of Endocrinology,
Department of Medicine, School of Medicine, University of Maryland, Baltimore,
MD 21201, USA. Electronic address: csztalry@grecc.umaryland.edu.
Cytosolic lipid storage droplets are primary functional organelles that regulate
cellular lipid metabolism and homeostasis. Paradoxically, excess lipid stores
are linked to both adaptive (fasting and chronic exercise) and mal-adaptive
(obesity and related health complications) conditions. Thus, collective
metabolic and physiological processes must balance lipid storage and utilization
with prevention of lipocytotoxicity and compounding tissue dysfunctions, urging
the need to further define the connection of mammalian lipid droplet function
and lipid homeostasis. The perilipins are a multi-protein family that targets
lipid droplet surfaces and regulates lipid storage and hydrolysis. Study of
perilipin functions has provided insight into the physiological roles of
cytosolic lipid droplets and their relationship with obesity-related
pathologies. Here, we review the current knowledge of the multiple perilipin
proteins in regulating tissue-specific lipid droplets and associations with
tissue and systemic energetics.
Published by Elsevier Masson SAS.
DOI: 10.1016/j.biochi.2013.08.026
PMCID: PMC4507817
PMID: 24036367 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22120990
|
1. Proteomics. 2012 Jan;12(2):241-5. doi: 10.1002/pmic.201100313. Epub 2011 Dec
20.
Investigating the macropinocytic proteome of Dictyostelium amoebae by
high-resolution mass spectrometry.
Journet A(1), Klein G, Brugière S, Vandenbrouck Y, Chapel A, Kieffer S, Bruley
C, Masselon C, Aubry L.
Author information:
(1)CEA, IRTSV, Laboratoire Biologie à Grande Echelle, Grenoble, France.
The cellular slime mold Dictyostelium discoideum is a soil-living eukaryote,
which feeds on microorganisms engulfed by phagocytosis. Axenic laboratory
strains have been produced that are able to use liquid growth medium
internalized by macropinocytosis as the source of food. To better define the
macropinocytosis process, we established the inventory of proteins associated
with this pathway using mass spectrometry-based proteomics. Using a magnetic
purification procedure and high-performance LC-MS/MS proteome analysis, a list
of 2108 non-redundant proteins was established, of which 24% featured
membrane-spanning domains. Bioinformatics analyses indicated that the most
abundant proteins were linked to signaling, vesicular trafficking and the
cytoskeleton. The present repertoire validates our purification method and paves
the way for a future proteomics approach to study the dynamics of
macropinocytosis.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/pmic.201100313
PMID: 22120990 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22522168
|
1. Yi Chuan. 2012 Apr;34(4):503-8. doi: 10.3724/sp.j.1005.2012.00503.
[Application of the Barr body case in teaching practice of genetics].
[Article in Chinese]
Chen FG(1), Hou BK.
Author information:
(1)Genetic teaching and research group, School of life science, Shandong
University, Jinan 250100, China. fanguo2002@sdu.edu.cn
There are three classical problems at the chromosome level in cytogenetics,
namely the formation mechanisms and effects of Barr body, polytenic chromosome,
and lampbrush chromosome. Teachers and researchers keep sustaining attention to
the Barr body because of the relationships between Barr body and the X
chromosome dosage compensation effect in mammals, the human sex identification,
and some human diseases. In our genetics teaching practice, we tried the
case-based teaching method. We introduced the classical problems and research
progress of the Barr body, as a line, into partial sections of our genetics
teaching contents such as sex-linked genetic analysis, eukaryotic gene
expression regulation, cancer genetic analysis, and genetic experiments.
Finally, it will form a comprehensive summary of related knowledge of genetics
through class discussion on the Barr body. We found that this teaching method
can not only optimize the teaching contents of genetics, consolidate and widen
students' basic knowledge, and help student to form the systemic and
developmental views of a classical genetics problem, but also inspire students'
interest in life sciences. Good teaching results have been achieved.
DOI: 10.3724/sp.j.1005.2012.00503
PMID: 22522168 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16806894
|
1. Curr Opin Biotechnol. 2006 Aug;17(4):406-14. doi:
10.1016/j.copbio.2006.06.004. Epub 2006 Jun 27.
Phosphoproteomic approaches to elucidate cellular signaling networks.
Schmelzle K(1), White FM.
Author information:
(1)Biological Engineering Division, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
Protein phosphorylation is crucial in the regulation of signaling pathways that
control various biological responses. Recent progress in diverse methodologies
to investigate protein phosphorylation in complex biological samples has
resulted in more rapid, detailed and quantitative analyses of signaling
networks. In particular, advances in mass spectrometry (MS) have enabled the
identification and quantification of thousands of both known and novel
phosphorylation sites. Initial MS-based information can be complemented with a
variety of recently developed and improved phosphoproteomic techniques. These
include multiplexed microbead or kinase activity assays, flow cytometry based
single-cell analysis, protein microarrays and interaction studies. The
combination of multiple approaches, coupled with phenotypic response
measurements, computational modeling and biochemical manipulations, will
ultimately reveal the mechanistic regulation of signaling networks.
DOI: 10.1016/j.copbio.2006.06.004
PMID: 16806894 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/17560583
|
1. J Chromatogr A. 2007 Aug 3;1159(1-2):81-109. doi:
10.1016/j.chroma.2007.05.048. Epub 2007 May 18.
Capillary electrophoresis-mass spectrometry for the analysis of intact proteins.
Haselberg R(1), de Jong GJ, Somsen GW.
Author information:
(1)Department of Biomedical Analysis, Utrecht University, 3508 TB Utrecht, The
Netherlands. r.haselberg@uu.nl
Developments in the fields of protein chemistry, proteomics and biotechnology
have increased the demand for suitable analytical techniques for the analysis of
intact proteins. In 1989, capillary electrophoresis (CE) was combined with mass
spectrometry (MS) for the first time and its potential usefulness for the
analysis of intact (i.e. non-digested) proteins was shown. This article provides
an overview of the applications of CE-MS within the field of intact protein
analysis. The principles of the applied CE modes and ionization techniques used
for CE-MS of intact proteins are shortly described. It is shown that separations
are predominantly carried out by capillary zone electrophoresis and capillary
isoelectric focusing, whereas electrospray ionization (ESI) and matrix-assisted
laser desorption ionization (MALDI) are the most popular ionization techniques
used for interfacing. The combination of CE with inductively coupled plasma
(ICP) MS for the analysis of metalloproteins is also discussed. The various
CE-MS combinations are systematically outlined and tables provide extensive
overviews of the applications of each technique for intact protein analysis.
Selected examples are given to illustrate the usefulness of the CE-MS
techniques. Examples include protein isoform assignment, single cell analysis,
metalloprotein characterization, proteomics and biomarker screening. Finally,
chip-based electrophoresis combined with MS is shortly treated and some of its
applications are described. It is concluded that CE-MS represents a powerful
tool for the analysis of intact proteins yielding unique separations and
information.
DOI: 10.1016/j.chroma.2007.05.048
PMID: 17560583 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20870251
|
1. Metabolism. 2011 Jun;60(6):852-9. doi: 10.1016/j.metabol.2010.08.004. Epub
2010 Sep 25.
High fatty acid availability after exercise alters the regulation of muscle
lipid metabolism.
Newsom SA(1), Schenk S, Li M, Everett AC, Horowitz JF.
Author information:
(1)School of Kinesiology, University of Michigan, Ann Arbor, MI 48109, USA.
We previously reported that a single exercise session protects against fatty
acid (FA)-induced insulin resistance, perhaps in part through augmented
intramyocellular triacylglycerol (IMTG) synthesis. The aim of this study was to
examine the effect of elevated FA availability after exercise on factors
regulating IMTG metabolism. After exercise (90 minutes, 65% peak oxygen uptake),
7 healthy women (body mass index, 23 ± 1 kg/m(2)) were infused overnight (16
hours) with either a lipid and heparin solution (LIPID, 0.11 g fat per kilogram
per hour) or saline (SALINE). We measured resting FA oxidation (indirect
calorimetry) and obtained a skeletal muscle biopsy sample the next morning. The
4-fold increase in overnight plasma FA concentration during LIPID increased IMTG
by approximately 30% during LIPID vs SALINE. This was accompanied by an
approximately 25% greater membrane-associated abundance of the FA transporter
FAT/CD36 (P < .01) and an approximately 8% increase in the activity of the IMTG
synthesis enzyme glycerol-3-phosphate acyltransferase (GPAT, P < .01). In
contrast, resting FA oxidation was not affected. We also found no difference in
the protein abundance of GPAT1 and diacylglycerol acyltransferase-1,
diacylglycerol acyltransferase activity, or the abundance of the lipid droplet
coat proteins (perilipins 2, 3, 4, and 5) between treatments. Our findings
suggest that augmented capacity for FA flux into muscle (ie, via
membrane-associated FAT/CD36), perhaps together with a slight yet significant
increase in activity of a key IMTG synthesis enzyme (GPAT), may enhance IMTG
storage when FA availability is high after exercise. The importance of the
absence of a change in perilipin protein abundance despite increased muscle
lipid storage remains to be determined.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.metabol.2010.08.004
PMCID: PMC3011035
PMID: 20870251 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest None of the authors had
any conflict of interest pertaining to the topic or contents of this article.
|
http://www.ncbi.nlm.nih.gov/pubmed/22629264
|
1. Front Plant Sci. 2011 Oct 12;2:54. doi: 10.3389/fpls.2011.00054. eCollection
2011.
Ultra performance liquid chromatography and high resolution mass spectrometry
for the analysis of plant lipids.
Hummel J(1), Segu S, Li Y, Irgang S, Jueppner J, Giavalisco P.
Author information:
(1)Max Planck Institute of Molecular Plant Physiology Potsdam, Germany.
Holistic analysis of lipids is becoming increasingly popular in the life
sciences. Recently, several interesting, mass spectrometry-based studies have
been conducted, especially in plant biology. However, while great advancements
have been made we are still far from detecting all the lipids species in an
organism. In this study we developed an ultra performance liquid
chromatography-based method using a high resolution, accurate mass, mass
spectrometer for the comprehensive profiling of more than 260 polar and
non-polar Arabidopsis thaliana leaf lipids. The method is fully compatible to
the commonly used lipid extraction protocols and provides a viable alternative
to the commonly used direct infusion-based shotgun lipidomics approaches. The
whole process is described in detail and compared to alternative lipidomic
approaches. Next to the developed method we also introduce an in-house developed
database search software (GoBioSpace), which allows one to perform targeted or
un-targeted lipidomic and metabolomic analysis on mass spectrometric data of
every kind.
DOI: 10.3389/fpls.2011.00054
PMCID: PMC3355513
PMID: 22629264
|
http://www.ncbi.nlm.nih.gov/pubmed/21151591
|
1. Biomark Insights. 2010 Nov 28;5:129-38. doi: 10.4137/BMI.S6184.
Biological functions of the genes in the mammaprint breast cancer profile
reflect the hallmarks of cancer.
Tian S(1), Roepman P, Van't Veer LJ, Bernards R, de Snoo F, Glas AM.
Author information:
(1)Agendia BV, Science Park 406, 1098 XH Amsterdam, The Netherlands.
BACKGROUND: MammaPrint was developed as a diagnostic tool to predict risk of
breast cancer metastasis using the expression of 70 genes. To better understand
the tumor biology assessed by MammaPrint, we interpreted the biological
functions of the 70-genes and showed how the genes reflect the six hallmarks of
cancer as defined by Hanahan and Weinberg.
RESULTS: We used a bottom-up system biology approach to elucidate how the
cellular processes reflected by the 70-genes work together to regulate tumor
activities and progression. The biological functions of the genes were analyzed
using literature research and several bioinformatics tools. Protein-protein
interaction network analyses indicated that the 70-genes form highly
interconnected networks and that their expression levels are regulated by key
tumorigenesis related genes such as TP53, RB1, MYC, JUN and CDKN2A. The
biological functions of the genes could be associated with the essential steps
necessary for tumor progression and metastasis, and cover the six well-defined
hallmarks of cancer, reflecting the acquired malignant characteristics of a
cancer cell along with tumor progression and metastasis-related biological
activities.
CONCLUSION: Genes in the MammaPrint gene signature comprehensively measure the
six hallmarks of cancer-related biology. This finding establishes a link between
a molecular signature and the underlying molecular mechanisms of tumor cell
progression and metastasis.
DOI: 10.4137/BMI.S6184
PMCID: PMC2999994
PMID: 21151591
|
http://www.ncbi.nlm.nih.gov/pubmed/18483364
|
1. Clin Cancer Res. 2008 May 15;14(10):2988-93. doi:
10.1158/1078-0432.CCR-07-4723.
Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal
cohort.
Wittner BS(1), Sgroi DC, Ryan PD, Bruinsma TJ, Glas AM, Male A, Dahiya S, Habin
K, Bernards R, Haber DA, Van't Veer LJ, Ramaswamy S.
Author information:
(1)Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114,
USA.
PURPOSE: Most node-negative breast cancer patients are older and postmenopausal
and are increasingly being offered adjuvant chemotherapy despite their low
overall risk of distant relapse. A molecular diagnostic test with high negative
predictive value (NPV) for distant metastasis in this subgroup would spare many
older breast cancer patients adjuvant treatment.
EXPERIMENTAL DESIGN: We determined the NPV and positive predictive value of the
MammaPrint assay in breast cancer patients who were consecutively diagnosed and
treated at the Massachusetts General Hospital between 1985 and 1997. Primary
tumors from 100 patients with node-negative, invasive breast cancer (median age,
62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis
and classified as being at either low or high risk for distant metastasis.
RESULTS: The MammaPrint 70-gene signature displayed excellent NPV as in previous
studies, correctly identifying 100% of women at low risk for distant metastases
at 5 years. However, this assay had a lower positive predictive value (12% at 5
years) than previously observed.
CONCLUSIONS: The MammaPrint assay was originally designed to identify younger
breast cancer patients at low risk for distant metastasis, who might
consequently be spared systemic treatment. We show here that the same signature
has a very high NPV for distant recurrence after adjuvant treatment in older
breast cancer patients.
DOI: 10.1158/1078-0432.CCR-07-4723
PMCID: PMC3089800
PMID: 18483364 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest
L.J.Van’t Veer, A.M. Glass, and T. Bruinsma are employed by Agendia BV. L.J.
Van’t Veer has an ownership interest in MammaPrint. L.J.Van’tVeer and R.
Bernards are named inventors on a patent to use microarray technology to
ascertain breast cancer prognosis and hold equity interests in Agendia BV.
|
http://www.ncbi.nlm.nih.gov/pubmed/19408941
|
1. Anal Chem. 2009 Jun 1;81(11):4356-68. doi: 10.1021/ac900241u.
Automated lipid identification and quantification by multidimensional mass
spectrometry-based shotgun lipidomics.
Yang K(1), Cheng H, Gross RW, Han X.
Author information:
(1)Division of Bioorganic Chemistry and Molecular Pharmacology, Washington
University School of Medicine, St. Louis, Missouri 63110, USA.
This article presents the strategies underlying the automated identification and
quantification of individual lipid molecular species through array analysis of
multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) data,
which are acquired directly from lipid extracts after direct infusion and
intrasource separation. The automated analyses of individual lipid molecular
species in the program employ a strategy in which MDMS-SL data from building
block analyses using precursor ion scans, neutral loss scans, or both are used
to identify individual molecular species, followed by quantitation. Through this
strategy, the program screens and identifies species in a high-throughput
fashion from a built-in database of over 36,000 potential lipid molecular
species constructed employing known building blocks. The program then uses a
two-step procedure for quantitation of the identified species possessing a
linear dynamic range over 3 orders of magnitude and reverifies the results when
necessary through redundant quantification of multidimensional mass spectra.
This program is designed to be easily adaptable for other shotgun lipidomics
approaches that are currently used for mass spectrometric analysis of lipids.
Accordingly, the development of this program should greatly accelerate
high-throughput analysis of lipids using MDMS-based shotgun lipidomics.
DOI: 10.1021/ac900241u
PMCID: PMC2728582
PMID: 19408941 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17953400
|
1. Subcell Biochem. 2007;43:301-21. doi: 10.1007/978-1-4020-5943-8_14.
Systems nanobiology: from quantitative single molecule biophysics to
microfluidic-based single cell analysis.
Martini J(1), Hellmich W, Greif D, Becker A, Merkle T, Ros R, Ros A, Toensing K,
Anselmetti D.
Author information:
(1)Experimental Biophysics and Applied Nanoscience, Physics Faculty, Bielefeld
University, Germany.
Detailed and quantitative information about structure-function relation,
concentrations and interaction kinetics of biological molecules and subcellular
components is a key prerequisite to understand and model cellular organisation
and temporal dynamics. In systems nanobi-ology, cellular processes are
quantitatively investigated at the sensitivity level of single molecules and
cells. This approach provides direct access to biomolecular information without
being statistically ensemble-averaged, their associated distribution functions,
and possible subpopulations. Moreover at the single cell level, the interplay of
regulated genomic information and proteomic variabilities can be investigated
and attributed to functional peculiarities. These requirements necessitate the
development of novel and ultrasensitive methods and instruments for single
molecule detection, microscopy and spectroscopy for analysis without the need of
amplification and preconcentration. In this chapter, we present three
methodological applications that demonstrate how quantitative informations can
be accessed that are representative for cellular processes or single cell
analysis like gene expression regulation, intracellular protein translocation
dynamics, and single cell protein fingerprinting. First, the interaction
kinetics of transcriptionally regulated DNA-protein interaction can be
quantitatively investigated with single molecule force spectroscopy allowing a
molecular affinity ranking. Second, intracellular protein dynamics for a
transcription regulator migrating form the nucleus to the cytoplasm can be
quantitatively monitored by photoactivable GFP and two-photon laser scanning
microscopy. And third, a microfluidic-based method for label-free single cell
proteomics and fingerprinting and first label-free single cell electropherograms
are presented which include the manipulation and steering of single cells in a
microfluidic device.
DOI: 10.1007/978-1-4020-5943-8_14
PMID: 17953400 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22738860
|
1. Breast. 2012 Dec;21(6):769-78. doi: 10.1016/j.breast.2012.04.010. Epub 2012
Jun 26.
Additional value of the 70-gene signature and levels of ER and PR for the
prediction of outcome in tamoxifen-treated ER-positive breast cancer.
Kok M(1), Koornstra RH, Mook S, Hauptmann M, Fles R, Jansen MP, Berns EM, Linn
SC, Van 't Veer LJ.
Author information:
(1)Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam,
The Netherlands.
BACKGROUND: Breast cancer patients with node positive disease can have an
excellent outcome with tamoxifen only. It is unclear whether analysing both the
70-gene signature and hormone receptors provides superior prediction of outcome
in tamoxifen-treated patients than either alone.
METHODS: Three series were evaluated: 121 patients (81% node positive) received
adjuvant tamoxifen, 151 patients did not receive tamoxifen (10% node positive)
and 92 patients received tamoxifen for metastatic disease. The 70-gene signature
was analysed using MammaPrint. Oestrogen receptor (ER) and progesterone receptor
(PR) immunohistochemistry was evaluated following St. Gallen Consensus (Highly
Endocrine Responsive: ER and PR ≥ 50%, Incompletely Endocrine Responsive: ER
and/or PR low or either one absent).
RESULTS: In patients treated with adjuvant tamoxifen, both the 70-gene signature
(adjusted for Endocrine Response Categories HR 2.17, 95%CI 1.01-4.66) as well as
the Endocrine Response Categories (adjusted for 70-gene signature HR 6.35, 95%CI
1.90-21.3) were associated with breast-cancer-specific-survival (BCSS). Also in
patients treated with tamoxifen for metastatic disease, combined analysis of the
70-gene signature and ER/PR revealed additional value (multivariate Cox
regression, p = 0.013). In patients who did not receive tamoxifen, only the
70-gene signature was associated with outcome.
CONCLUSION: In the series analysed, the 70-gene signature was mainly a
prognostic factor, while ER and PR levels were mainly associated with outcome
after tamoxifen. Combination of these three factors may improve outcome
prediction in tamoxifen-treated patients.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.breast.2012.04.010
PMID: 22738860 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20680590
|
1. Methods Mol Biol. 2010;656:159-71. doi: 10.1007/978-1-60761-746-4_9.
Laser ablation electrospray ionization for atmospheric pressure molecular
imaging mass spectrometry.
Nemes P(1), Vertes A.
Author information:
(1)Department of Chemistry, W. M. Keck Institute for Proteomics Technology and
Applications, George Washington University, Washington, DC, USA.
Laser ablation electrospray ionization (LAESI) is a novel method for the direct
imaging of biological tissues by mass spectrometry. By performing ionization in
the ambient environment, this technique enables in vivo studies with potential
for single-cell analysis. A unique aspect of LAESI mass spectrometric imaging
(MSI) is depth profiling that, in combination with lateral imaging, permits 3D
molecular imaging for the first time under native conditions. With current
lateral and depth resolutions of approximately 100 and approximately 40 microm,
respectively, LAESI MSI helps to explore the molecular architecture of live
tissues.
DOI: 10.1007/978-1-60761-746-4_9
PMID: 20680590 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22946708
|
1. J Agric Food Chem. 2012 Sep 19;60(37):9384-93. doi: 10.1021/jf303181s. Epub
2012 Sep 10.
Shotgun lipidomics strategy for fast analysis of phospholipids in fisheries
waste and its potential in species differentiation.
Shen Q(1), Wang Y, Gong L, Guo R, Dong W, Cheung HY.
Author information:
(1)Department of Chemistry and Biology, City University of Hong Kong, Kowloon,
Hong Kong SAR, China.
An efficient shotgun lipidomics strategy was established and optimized for fast
phospholipid profiling of viscera from three fish species: Lateolabrax
japonicas, Ctenopharyngodon idellus, and Carassius auratus. This strategy relies
on direct infusion of total lipid extracts into a tandem mass spectrometer
without additional separation of the individual molecular species. Four classes
of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine
(PE), phosphatidylinositol (PI), and phosphatidylserine (PS), were analyzed, and
at least 81 molecular species of phospholipids were identified, including 34
species of PC, 24 species of PE, 12 species of PS, and 11 species of PI, in both
positive- and negative-ion electrospray ionization mode. The results show that
fish viscera, which are traditionally discarded as fisheries wastes, are
nutritional in phospholipids with total contents of the four detected
phospholipid classes ranging from 1.52 to 3.29 mg/g in the three tested fish
species. Regardless of the tested fish species, PC and PE are the dominant
phospholipid classes, followed by PI and PS. Furthermore, principal component
analysis (PCA) was applied to normalize the relative amounts of the identified
phospholipid species. The results demonstrate that PS 18:0/22:6, PI 18:0/20:4,
and PI 18:0/20:5 were the main contributors of cumulative value and could be
used as an indicator for fish species differentiation. This shotgun lipidomics
method was >10 times faster than traditional methods, because no chromatographic
separation was needed. The successful application of this strategy paves the way
for full utilization of traditionally discarded fisheries wastes and provides an
alternative means for fish species differentiation.
DOI: 10.1021/jf303181s
PMID: 22946708 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18786252
|
1. BMC Med Genomics. 2008 Sep 11;1:39. doi: 10.1186/1755-8794-1-39.
Identification of a gene signature in cell cycle pathway for breast cancer
prognosis using gene expression profiling data.
Liu J(1), Campen A, Huang S, Peng SB, Ye X, Palakal M, Dunker AK, Xia Y, Li S.
Author information:
(1)Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285,
USA. liu_jiangang@lilly.com
BACKGROUND: Numerous studies have used microarrays to identify gene signatures
for predicting cancer patient clinical outcome and responses to chemotherapy.
However, the potential impact of gene expression profiling in cancer diagnosis,
prognosis and development of personalized treatment may not be fully exploited
due to the lack of consensus gene signatures and poor understanding of the
underlying molecular mechanisms.
METHODS: We developed a novel approach to derive gene signatures for breast
cancer prognosis in the context of known biological pathways. Using unsupervised
methods, cancer patients were separated into distinct groups based on gene
expression patterns in one of the following pathways: apoptosis, cell cycle,
angiogenesis, metastasis, p53, DNA repair, and several receptor-mediated
signaling pathways including chemokines, EGF, FGF, HIF, MAP kinase, JAK and
NF-kappaB. The survival probabilities were then compared between the patient
groups to determine if differential gene expression in a specific pathway is
correlated with differential survival.
RESULTS: Our results revealed expression of cell cycle genes is strongly
predictive of breast cancer outcomes. We further confirmed this observation by
building a cell cycle gene signature model using supervised methods. Validated
in multiple independent datasets, the cell cycle gene signature is a more
accurate predictor for breast cancer clinical outcome than the previously
identified Amsterdam 70-gene signature that has been developed into a FDA
approved clinical test MammaPrint.
CONCLUSION: Taken together, the gene expression signature model we developed
from well defined pathways is not only a consistently powerful prognosticator
but also mechanistically linked to cancer biology. Our approach provides an
alternative to the current methodology of identifying gene expression markers
for cancer prognosis and drug responses using the whole genome gene expression
data.
DOI: 10.1186/1755-8794-1-39
PMCID: PMC2551605
PMID: 18786252
|
http://www.ncbi.nlm.nih.gov/pubmed/21811421
|
1. PLoS Genet. 2011 Jul;7(7):e1002212. doi: 10.1371/journal.pgen.1002212. Epub
2011 Jul 21.
The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as
ever.
Morey C(1), Avner P.
Author information:
(1)Institut Pasteur, Unité de Génétique Moléculaire Murine, CNRS, URA2578,
Paris, France.
In humans, sexual dimorphism is associated with the presence of two X
chromosomes in the female, whereas males possess only one X and a small and
largely degenerate Y chromosome. How do men cope with having only a single X
chromosome given that virtually all other chromosomal monosomies are lethal?
Ironically, or even typically many might say, women and more generally female
mammals contribute most to the job by shutting down one of their two X
chromosomes at random. This phenomenon, called X-inactivation, was originally
described some 50 years ago by Mary Lyon and has captivated an increasing number
of scientists ever since. The fascination arose in part from the realisation
that the inactive X corresponded to a dense heterochromatin mass called the
"Barr body" whose number varied with the number of Xs within the nucleus and
from the many intellectual questions that this raised: How does the cell count
the X chromosomes in the nucleus and inactivate all Xs except one? What kind of
molecular mechanisms are able to trigger such a profound, chromosome-wide
metamorphosis? When is X-inactivation initiated? How is it transmitted to
daughter cells and how is it reset during gametogenesis? This review retraces
some of the crucial findings, which have led to our current understanding of a
biological process that was initially considered as an exception completely
distinct from conventional regulatory systems but is now viewed as a paradigm
"par excellence" for epigenetic regulation.
DOI: 10.1371/journal.pgen.1002212
PMCID: PMC3141017
PMID: 21811421 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/22203961
|
1. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):419-24. doi:
10.1073/pnas.1110865109. Epub 2011 Dec 27.
Single-cell proteomic chip for profiling intracellular signaling pathways in
single tumor cells.
Shi Q(1), Qin L, Wei W, Geng F, Fan R, Shin YS, Guo D, Hood L, Mischel PS, Heath
JR.
Author information:
(1)Nanosystems Biology Cancer Center, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
We describe a microchip designed to quantify the levels of a dozen cytoplasmic
and membrane proteins from single cells. We use the platform to assess
protein-protein interactions associated with the EGF-receptor-mediated PI3K
signaling pathway. Single-cell sensitivity is achieved by isolating a defined
number of cells (n = 0-5) in 2 nL volume chambers, each of which is patterned
with two copies of a miniature antibody array. The cells are lysed on-chip, and
the levels of released proteins are assayed using the antibody arrays. We
investigate three isogenic cell lines representing the cancer glioblastoma
multiforme, at the basal level, under EGF stimulation, and under erlotinib
inhibition plus EGF stimulation. The measured protein abundances are consistent
with previous work, and single-cell analysis uniquely reveals single-cell
heterogeneity, and different types and strengths of protein-protein
interactions. This platform helps provide a comprehensive picture of altered
signal transduction networks in tumor cells and provides insight into the effect
of targeted therapies on protein signaling networks.
DOI: 10.1073/pnas.1110865109
PMCID: PMC3258586
PMID: 22203961 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/23117646
|
1. Rev Clin Esp. 2012 Jan;212 Suppl 1:3-7. doi: 10.1016/S0014-2565(12)70010-3.
[New advances in anticoagulation: is it time to forget about heparin and vitamin
K antagonists? Yes].
[Article in Spanish]
Blanco-Molina A(1).
Author information:
(1)Unidad Clínica de Gestión de Medicina Interna, Hospital Universitario Reina
Sofía, Córdoba, España. mablancom@telefonica.net
Comment in
Rev Clin Esp. 2012 Jan;212 Suppl 1:8-11. doi: 10.1016/S0014-2565(12)70011-5.
For the last 60 years, heparin and vitamin K antagonists have been the
cornerstone of anticoagulation. Nowadays, the new anticoagulants, such as
dabigatran, rivaroxaban and apixaban, show potential advantages over classical
treatments. These agents inhibit specific coagulation factors and are
administered orally at fixed doses. Furthermore, heparin and vitamin K
antagonists have a fast onset of action, short-duration and predictable
therapeutic effects. No interactions with foods have been described, although
some drug-drug interactions have been reported. At the moment, no antidotes are
available. However, due to the short half-life of these agents, antidotes are
less essential. The new anticoagulants are at least as effective and safe as
traditional treatments in the prevention of venous thromboembolism after
orthopedic surgery, as well as in the prevention of stroke and systemic embolism
in non-valvular atrial fibrillation. Dabigatran and rivaroxaban have also been
shown to be effective in the treatment of acute venous thromboembolism. Due to
their properties, these drugs could gradually replace heparin and especially
vitamin K antagonists. Hopefully, many of our patients will be able to
discontinue classical anticoagulant treatment and others will never begin it.
Copyright © 2012 Elsevier España, S.L. All rights reserved.
DOI: 10.1016/S0014-2565(12)70010-3
PMID: 23117646 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23776651
|
1. PLoS One. 2013 Jun 11;8(6):e66270. doi: 10.1371/journal.pone.0066270. Print
2013.
Inflammation and resolution are associated with upregulation of fatty acid
β-oxidation in Zymosan-induced peritonitis.
Fujieda Y(1), Manno A, Hayashi Y, Rhodes N, Guo L, Arita M, Bamba T, Fukusaki E.
Author information:
(1)Department of Biotechnology, Graduate School of Engineering, Osaka
University, Suita, Japan ; Asubio Pharma Co., Limited, Kobe, Japan.
fujieda.yusuke.aw@asubio.co.jp
Inflammation is a fundamental defensive response to harmful stimuli. However, it
can cause damage if it does not subside. To avoid such damage, organisms have
developed a mechanism called resolution of inflammation. Here we applied an
untargeted metabolomics approach to a sterile and self-resolving animal model of
acute inflammation, namely zymosan-induced peritonitis in mice, to examine the
effect of inflammation and resolution on the metabolomic profiles. Significant
and time-dependent changes in metabolite profiles after zymosan administration
were observed in both peritoneal wash fluid (PWF) and plasma. These metabolomic
changes correlated well with inflammatory chemokine or cytokine production. In
PWF, most of metabolites that could detected increased in zymosan-treated mice,
which is suggestive of inflammation, oxidative stress and increased energy
demands. In plasma, most metabolites in the central metabolic pathway
(glycolysis and TCA cycle) were significantly downregulated after zymosan
administration. The concentration of the ketone body 3-hydroxybutyric acid
(3-HB) in plasma and PWF increased in zymosan-injected animals indicating
upregulation of fatty acid β-oxidation. Increased 3-HB level was observed in the
cells that infiltrated into the peritoneal cavity and these infiltrated cells
might contribute, at least in part, to the production of 3-HB in the peritoneal
cavity.
DOI: 10.1371/journal.pone.0066270
PMCID: PMC3679047
PMID: 23776651 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have read the
journal's policy and have the following conflicts: YF, MA and YH are employees
of Aubio Phama CO., LTD. NR and LG are employees of Metabolon Inc. This does not
alter the authors' adherence to all journal policies on sharing data and
materials.
|
http://www.ncbi.nlm.nih.gov/pubmed/21523508
|
1. Inflamm Res. 2011 Sep;60(9):831-40. doi: 10.1007/s00011-011-0340-7. Epub 2011
Apr 27.
GC/MS-based profiling of amino acids and TCA cycle-related molecules in
ulcerative colitis.
Ooi M(1), Nishiumi S, Yoshie T, Shiomi Y, Kohashi M, Fukunaga K, Nakamura S,
Matsumoto T, Hatano N, Shinohara M, Irino Y, Takenawa T, Azuma T, Yoshida M.
Author information:
(1)Division of Gastroenterology, Department of Internal Medicine, Kobe
University Graduate School of Medicine, 7-5-1, Chuo-ku, Kusunoki-cho, Kobe,
Hyogo, 650-0017, Japan.
OBJECTIVE: The roles that amino acids play in immunity and inflammation are well
defined, and the relationship between inflammatory bowel disease (IBD) and
certain amino acids has recently attracted attention. In this study, the levels
of amino acids and trichloroacetic acid (TCA) cycle-related molecules in the
colonic tissues and sera of patients with ulcerative colitis (UC) were profiled
by gas chromatography/mass spectrometry (GC/MS), with the aim of evaluating
whether the clinical state induced by UC leads to variations in the amino acid
profile.
MATERIALS AND METHODS: Colonic biopsy samples from 22 UC patients were used, as
well as serum samples from UC patients (n = 13), Crohn's disease (CD) patients
(n = 21), and healthy volunteers (n = 17).
RESULTS: In the GC/MS-based profiling of amino acids and TCA cycle-related
molecules, lower levels of 16 amino acids and 5 TCA cycle-related molecules were
observed in the colonic lesion tissues of the UC patients, and the serum
profiles of amino acids and TCA cycle-related molecules of the UC patients were
different from those of the CD patients and healthy volunteers.
CONCLUSIONS: Our study raises the possibility that GC/MS-based profiling of
amino acids and TCA cycle-related molecules is a useful early diagnostic tool
for UC.
DOI: 10.1007/s00011-011-0340-7
PMID: 21523508 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18393142
|
1. Semin Thromb Hemost. 2008 Feb;34(1):39-57. doi: 10.1055/s-2008-1066023.
Current and future prospects for anticoagulant therapy: inhibitors of factor Xa
and factor IIa.
Harenberg J(1), Wehling M.
Author information:
(1)Clinical Pharmacology Mannheim, Vascular Pharmacotherapy, Faculty of
Medicine, University of Heidelberg, Mannheim, Germany.
job.harenberg@med.ma.uni-heidelberg.de
Indirect systemic and direct oral factor Xa and direct oral factor IIa
inhibitors with improved pharmacologic profiles compared with heparins and
vitamin K antagonists are currently in clinical development. This overview
focuses on the indirect antithrombin dependent pentasaccharide derivatives of
idraparinux and on the most advanced oral direct inhibitors to factor Xa
(rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of
dose-finding studies for the prevention of venous thromboembolism after elective
orthopedic surgery, the results of dose-finding studies for treatment of acute
venous thromboembolism including prolonged prophylaxis of recurrent events, and
the designs of ongoing clinical trials are reviewed.
DOI: 10.1055/s-2008-1066023
PMID: 18393142 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17920553
|
1. Anal Biochem. 2007 Dec 15;371(2):135-45. doi: 10.1016/j.ab.2007.08.019. Epub
2007 Aug 22.
Alkaline methanolysis of lipid extracts extends shotgun lipidomics analyses to
the low-abundance regime of cellular sphingolipids.
Jiang X(1), Cheng H, Yang K, Gross RW, Han X.
Author information:
(1)Division of Bioorganic Chemistry and Molecular Pharmacology, Department of
Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
63110, USA.
Sphingolipids that contain a sphingoid base are composed of hundreds to
thousands of distinct compounds, many of which serve as lipid regulators of
biological functions. The global analysis of the large number of low-abundance
sphingolipid molecular species has been hampered in many cases by the
sphingolipid molecular species being overwhelmed by the quantity of other
classes of lipid (e.g., glycerophospholipid) molecular species present, thereby
imposing severe restrictions on the dynamic range of their measurement using
shotgun lipidomics. Herein, we developed a facile approach in which the
sphingolipids of cellular extracts were dramatically enriched by direct alkaline
methanolysis of lipid extracts followed by extraction to remove the large
majority of other endogenous lipid classes. Through direct infusion of the
resultant enriched solution, we identified and quantitated a variety of
very-low-abundance sphingolipid classes (e.g., sphingosine, psychosine, and
lysosphingomyelin) and molecular species (e.g., sphingomyelin) using
electrospray ionization mass spectrometry (i.e., shotgun sphingolipidomics).
Accordingly, through utilization of these facile enrichment techniques, direct
penetrance into the sphingolipidomes has been greatly extended, facilitating new
insights into their metabolism and signaling functions in biological systems.
DOI: 10.1016/j.ab.2007.08.019
PMCID: PMC2131739
PMID: 17920553 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17439240
|
1. Anal Chem. 2007 May 15;79(10):3690-4. doi: 10.1021/ac062411p. Epub 2007 Apr
18.
Single-cell peptidomics of drosophila melanogaster neurons identified by
Gal4-driven fluorescence.
Neupert S(1), Johard HA, Nässel DR, Predel R.
Author information:
(1)Institute of Zoology, Friedrich-Schiller-University Jena, Erbertstrasse 1,
07743 Jena, Germany.
Erratum in
Anal Chem. 2012 Jun 5;84(11):5164.
Neuropeptides are widespread signal molecules that display a great chemical and
functional diversity. Predictions of neuropeptide cleavage from precursor
proteins are not always correct, and thus, biochemical identification is
essential. Single-cell analysis is valuable to identify peptides processed from
a single precursor, but also to determine coexpression of further neuropeptides
from other precursors. We have developed an approach to isolate single
identified neurons from the fruit fly Drosophila melanogaster for mass
spectrometric analysis. By using Gal4 promoter lines to drive green fluorescent
protein under UAS control, we identified specific peptidergic neurons. These
neurons were isolated singly under a fluorescence microscope and subjected to
MALDI-TOF mass spectrometry. Two Gal4 lines were used here to identify
pigment-dispersing factor (PDF) and hugin-expressing neurons. We found that the
large PDF expressing clock neurons only give rise to a single peptide, PDF. The
three different classes of hugin expressing neurons all display the same mass
signal, identical to pyrokinin-2. The other peptide predicted from the hugin
precursor, hugin gamma, was not detected in any of the cells. Single-cell
peptidomics is a powerful tool in Drosophila neuroscience since Gal4 drivers can
be produced for all known neuropeptide genes and thus provide detailed
information about neuropeptide complements in neurons of interest.
DOI: 10.1021/ac062411p
PMID: 17439240 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24727425
|
1. Int J Biochem Cell Biol. 2014 Jun;51:93-101. doi:
10.1016/j.biocel.2014.03.032. Epub 2014 Apr 13.
Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a
mouse model.
Homedan C(1), Laafi J(2), Schmitt C(3), Gueguen N(4), Lefebvre T(3), Karim Z(3),
Desquiret-Dumas V(4), Wetterwald C(5), Deybach JC(3), Gouya L(3), Puy H(3),
Reynier P(6), Malthièry Y(1).
Author information:
(1)UMR INSERM 1063, Angers, France; Centre Hospitalier Universitaire,
Département de Biochimie et Génétique, Angers, France.
(2)UMR INSERM 1063, Angers, France.
(3)Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries,
Hôpital Louis Mourier, Université Paris Diderot, Colombes, France; INSERM U1149,
Center for Research on Inflammation (CRI), Université Paris Diderot, Paris,
France; Laboratory of Excellence, GR-Ex, Paris, France.
(4)Centre Hospitalier Universitaire, Département de Biochimie et Génétique,
Angers, France; UMR CNRS 6214-INSERM 1083, Angers, France.
(5)Centre Hospitalier Universitaire, Département de Biochimie et Génétique,
Angers, France.
(6)Centre Hospitalier Universitaire, Département de Biochimie et Génétique,
Angers, France; UMR CNRS 6214-INSERM 1083, Angers, France. Electronic address:
pareynier@chu-angers.fr.
Acute intermittent porphyria (AIP), an inherited hepatic disorder, is due to a
defect of hydroxymethylbilane synthase (HMBS), an enzyme involved in heme
biosynthesis. AIP is characterized by recurrent, life-threatening attacks at
least partly due to the increased hepatic production of 5-aminolaevulinic acid
(ALA). Both the mitochondrial enzyme, ALA synthase (ALAS) 1, involved in the
first step of heme biosynthesis, which is closely linked to mitochondrial
bioenergetic pathways, and the promise of an ALAS1 siRNA hepatic therapy in
humans, led us to investigate hepatic energetic metabolism in Hmbs KO mice
treated with phenobarbital. The mitochondrial respiratory chain (RC) and the
tricarboxylic acid (TCA) cycle were explored in the Hmbs(-/-) mouse model. RC
and TCA cycle were significantly affected in comparison to controls in mice
treated with phenobarbital with decreased activities of RC complexes I (-52%,
(**)p<0.01), II (-50%, (**)p<0.01) and III (-55%, (*)p<0.05), and decreased
activity of α-ketoglutarate dehydrogenase (-64%, (*)p<0.05), citrate synthase
(-48%, (**)p<0.01) and succinate dehydrogenase (-53%, (*)p<0.05). Complex
II-driven succinate respiration was also significantly affected. Most of these
metabolic alterations were at least partially restored after the phenobarbital
arrest and heme arginate administration. These results suggest a cataplerosis of
the TCA cycle induced by phenobarbital, caused by the massive withdrawal of
succinyl-CoA by ALAS induction, such that the TCA cycle is unable to supply the
reduced cofactors to the RC. This profound and reversible impact of AIP on
mitochondrial energetic metabolism offers new insights into the beneficial
effect of heme, glucose and ALAS1 siRNA treatments by limiting the cataplerosis
of TCA cycle.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.biocel.2014.03.032
PMID: 24727425 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24361092
|
1. Trends Cell Biol. 2014 May;24(5):313-20. doi: 10.1016/j.tcb.2013.11.008. Epub
2013 Dec 19.
Succinate: a metabolic signal in inflammation.
Mills E(1), O'Neill LA(2).
Author information:
(1)School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute,
Trinity College Dublin, Dublin 2, Ireland.
(2)School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute,
Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.
Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a
crucial role in adenosine triphosphate (ATP) generation in mitochondria.
Recently, new roles for succinate outside metabolism have emerged. Succinate
stabilizes the transcription factor hypoxia-inducible factor-1α (HIF-1α) in
specific tumors and in activated macrophages, and stimulates dendritic cells via
its receptor succinate receptor 1. Furthermore, succinate has been shown to
post-translationally modify proteins. This expanding repertoire of functions for
succinate suggests a broader role in cellular activation. We review the new
roles of succinate and draw parallels to other metabolites such as NAD(+) and
citrate whose roles have expanded beyond metabolism and into signaling.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2013.11.008
PMID: 24361092 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19126254
|
1. Int J Technol Assess Health Care. 2009 Jan;25(1):73-83. doi:
10.1017/S0266462309090102.
Constructive Technology Assessment (CTA) as a tool in coverage with evidence
development: the case of the 70-gene prognosis signature for breast cancer
diagnostics.
Retèl VP(1), Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF,
Karsenberg K, van Dam FS, van Krimpen C, Bellot FE, Roumen RM, Linn SC, van
Harten WH.
Author information:
(1)Department of Psychosocial Research and Epidemiology, Netherlands Cancer
Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
v.retel@nki.nl
OBJECTIVES: Constructive Technology Assessment (CTA) is a means to guide early
implementation of new developments in society, and can be used as an evaluation
tool for Coverage with Evidence Development (CED). We used CTA for the
introduction of a new diagnostic test in the Netherlands, the 70-gene prognosis
signature (MammaPrint) for node-negative breast cancer patients.
METHODS: Studied aspects were (organizational) efficiency, patient-centeredness
and diffusion scenarios. Pre-post structured surveys were conducted in fifteen
community hospitals concerning changes in logistics and teamwork as a
consequence of the introduction of the 70-gene signature. Patient-centeredness
was measured by questionnaires and interviews regarding knowledge and
psychological impact of the test. Diffusion scenarios, which are commonly
applied in industry to anticipate on future development and diffusion of their
products, have been applied in this study.
RESULTS: Median implementation-time of the 70-gene signature was 1.2 months.
Most changes were seen in pathology processes and adjuvant treatment decisions.
Physicians valued the addition of the 70-gene signature information as
beneficial for patient management. Patient-centeredness (n = 77, response 78
percent): patients receiving a concordant high-risk and discordant clinical
low/high risk-signature showed significantly more negative emotions with respect
to receiving both test-results compared with concordant low-risk and discordant
clinical high/low risk-signature patients. The first scenario was written in
2004 before the introduction of the 70-gene signature and identified
hypothetical developments that could influence diffusion; especially the
"what-if" deviation describing a discussion on validity among physicians proved
to be realistic.
CONCLUSIONS: Differences in speed of implementation and influenced treatment
decisions were seen. Impact on patients seems especially related to discordance
and its successive communication. In the future, scenario drafting will lead to
input for model-based cost-effectiveness analysis. Finally, CTA can be useful as
a tool to guide CED by adding monitoring and anticipation on possible
developments during early implementation, to the assessment of promising new
technologies.
DOI: 10.1017/S0266462309090102
PMID: 19126254 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22084658
|
1. Thrombosis. 2010;2010:280731. doi: 10.1155/2010/280731. Epub 2010 Jul 29.
New oral anticoagulants for thromboprophylaxis after elective total hip and knee
arthroplasty.
Friedman RJ(1).
Author information:
(1)Department of Orthopaedic Surgery, Roper Hospital, Charleston Orthopaedic
Associates, 1012 Physicians Drive, Charleston, SC 29414, USA.
Anticoagulant drugs reduce the risk of venous thromboembolic events after total
hip and knee arthroplasty. However, the use of current drugs, such as low
molecular weight heparins, is hampered by their subcutaneous route of
administration. The use of vitamin K antagonists is hampered by the requirement
for routine coagulation monitoring and dose titration to provide effective
anticoagulation without an increased risk of bleeding and numerous food and drug
interactions. Clearly, there is a need for new oral, fixed-dose anticoagulant
drugs that do not require coagulation monitoring, while demonstrating similar or
better efficacy and safety profiles when compared with current agents.
DOI: 10.1155/2010/280731
PMCID: PMC3211075
PMID: 22084658
|
http://www.ncbi.nlm.nih.gov/pubmed/22153026
|
1. Semin Vasc Surg. 2011 Sep;24(3):157-61. doi:
10.1053/j.semvascsurg.2011.11.003.
Direct thrombin inhibitors for the treatment of venous thromboembolism: analysis
of the Dabigatran versus Warfarin clinical trial.
Liem TK(1), Deloughery TG.
Author information:
(1)Division of Vascular Surgery, Oregon Health and Science University, Portland,
OR 97239, USA. Liemt@ohsu.edu
Vitamin-K antagonists have played a dominant role in the long-term management of
patients with venous thromboembolism, and large trials from the past decade
reinforced warfarin's effectiveness as an intermediate-duration and
extended-duration anticoagulant. However, promising new oral direct thrombin
inhibitors are proving to be at least as effective and as safe as the vitamin-K
antagonists, without the associated hepatic toxicity that was seen with earlier
orally administered direct thrombin inhibitors. This article reviews the
recently published Dabigatran versus Warfarin in the Treatment of Acute Venous
Thromboembolism clinical trial, and discusses the limitations and clinical
applicability of the trial, especially in comparison with vitamin-K antagonists
and the recently studied oral direct factor Xa inhibitors, rivaroxaban and
apixaban.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1053/j.semvascsurg.2011.11.003
PMID: 22153026 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23825371
|
1. Bioinformatics. 2013 Oct 1;29(19):2445-51. doi: 10.1093/bioinformatics/btt376.
Epub 2013 Jul 3.
Statistical agglomeration: peak summarization for direct infusion lipidomics.
Smith R(1), Anthonymuthu TS, Ventura D, Prince JT.
Author information:
(1)Department of Computer Science and Department of Chemistry, Brigham Young
University, Provo, UT 84602, USA.
MOTIVATION: Quantification of lipids is a primary goal in lipidomics. In direct
infusion/injection (or shotgun) lipidomics, accurate downstream identification
and quantitation requires accurate summarization of repetitive peak
measurements. Imprecise peak summarization multiplies downstream error by
propagating into species identification and intensity estimation. To our
knowledge, this is the first analysis of direct infusion peak summarization in
the literature.
RESULTS: We present two novel peak summarization algorithms for direct infusion
samples and compare them with an off-machine ad hoc summarization algorithm as
well as with the propriety Xcalibur algorithm. Our statistical agglomeration
algorithm reduces peakwise error by 38% mass/charge (m/z) and 44% (intensity)
compared with the ad hoc method over three datasets. Pointwise error is reduced
by 23% (m/z). Compared with Xcalibur, our statistical agglomeration algorithm
produces 68% less m/z error and 51% less intensity error on average on two
comparable datasets.
AVAILABILITY: The source code for Statistical Agglomeration and the datasets
used are freely available for non-commercial purposes at
https://github.com/optimusmoose/statistical_agglomeration. Modified Bin
Aggolmeration is freely available in MSpire, an open source mass spectrometry
package at https://github.com/princelab/mspire/.
DOI: 10.1093/bioinformatics/btt376
PMID: 23825371 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25150282
|
1. Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):2032-40. doi:
10.1158/1055-9965.EPI-13-0957. Epub 2014 Aug 22.
Reduced nicotine cigarettes: smoking behavior and biomarkers of exposure among
smokers not intending to quit.
Hammond D(1), O'Connor RJ(2).
Author information:
(1)School of Public Health and Health Systems, University of Waterloo, Ontario,
Canada. dhammond@uwaterloo.ca.
(2)Department of Health Behavior, Roswell Park Cancer Institute, Buffalo, New
York.
BACKGROUND: The U.S. FDA has the authority to limit the nicotine content of
cigarettes; however, there are concerns that reduced nicotine cigarettes will be
smoked more intensely and, therefore, will increase exposure to toxic chemicals
in smoke. This study examined changes in consumer behavior and exposure in
response to cigarettes with substantially reduced nicotine content.
METHODS: Seventy-two adult smokers completed an unblinded trial of reduced
nicotine cigarettes. Participants completed a 7-day baseline period during which
they smoked their usual cigarette brand, followed by consecutive 7-day periods
smoking cigarettes with progressively lower nicotine levels (0.6, 0.3, and 0.05
mg emission Quest cigarettes). Nicotine dependence and withdrawal, smoking
behavior, and biomarkers of exposure were assessed for each 7-day period.
RESULTS: Significant reductions in nicotine intake were observed between usual
brand smoking (∼1.2 mg nicotine) and the 0.3 and 0.05 mg nicotine emission
cigarettes, but not the 0.6 mg cigarette. The findings provide little evidence
of compensatory smoking of Quest cigarettes, with no increases in exhaled breath
carbon monoxide levels, smoking intensity, or levels of 1-hydroxypyrene across
study periods. No significant differences were observed for smoking urges or
measures of nicotine dependence.
CONCLUSIONS: The study adds to the evidence that cigarettes with markedly
reduced nicotine content are not associated with increased smoking intensity or
exposure to smoke toxicants.
IMPACT: The findings add to the evidence base on reduced nicotine content
cigarettes and have the potential to inform FDA policy on nicotine levels.
©2014 American Association for Cancer Research.
DOI: 10.1158/1055-9965.EPI-13-0957
PMID: 25150282 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16497603
|
1. Nicotine Tob Res. 2006 Feb;8(1):89-101. doi: 10.1080/14622200500431866.
Precessation treatment with nicotine skin patch facilitates smoking cessation.
Rose JE(1), Behm FM, Westman EC, Kukovich P.
Author information:
(1)Nicotine Research Program, VA Medical Center and Department of Psychiatry,
Duke University Medical Center, Durham, NC 27705, USA. rose0003@mc.duke.edu
Nicotine replacement therapy (NRT) is a well-established treatment to aid
smoking cessation, and current products recommend using NRT only after quitting
smoking. However, theoretical arguments and previous data support the hypothesis
that precessation use of NRT might be useful in reducing dependence on inhaled
nicotine and serve as a helpful prelude to smoking cessation. The present study
explored the use of NRT for 2 weeks before a target quit-smoking date, during
which subjects continued to smoke ad libitum. Three experimental conditions
varied the nicotine delivery of the cigarettes smoked during these 2 weeks so
that we could examine the effects of concurrent nicotine administration on
compensatory smoking of low tar and nicotine cigarettes. Subjects smoked (a)
their usual brands of cigarettes, (b) conventional low tar and nicotine
cigarettes, or (c) denicotinized cigarettes. After the quit date, subjects
received pharmacotherapy consisting of various doses of NRT (0, 21, or 42
mg/24-hr) in combination with the nicotinic antagonist mecamylamine (10 mg/day).
Results showed that precessation nicotine patch treatment was associated with a
significantly higher rate of continuous smoking abstinence at 4 weeks,
regardless of cigarette condition. Ad libitum smoking before the target quit
date was modulated by nicotine patch treatment, and compensatory increases in
smoking low tar and nicotine cigarettes were prevented by concurrent use of
nicotine patches. These results suggest that use of NRT before a target
quit-smoking date deserves further evaluation as a possible smoking cessation
treatment. Moreover, while nicotine patches were well tolerated when subjects
smoked nicotine-containing cigarettes, the use of nicotine skin patches with
reduced-nicotine cigarettes potentially offers the advantage of increased
efficacy without introducing concern about toxic effects of excessive nicotine
intake.
DOI: 10.1080/14622200500431866
PMID: 16497603 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24746485
|
1. Addict Behav. 2014 Jul;39(7):1197-204. doi: 10.1016/j.addbeh.2014.03.021. Epub
2014 Mar 30.
Sex differences in response to reduced nicotine content cigarettes.
Vogel RI(1), Hertsgaard LA(2), Dermody SS(3), Luo X(4), Moua L(2), Allen S(5),
al'Absi M(6), Hatsukami DK(7).
Author information:
(1)University of Minnesota, Masonic Comprehensive Cancer Center, Minneapolis,
MN, United States.
(2)University of Minnesota, Tobacco Research Programs, Minneapolis, MN, United
States.
(3)University of Pittsburgh, Department of Psychology, Pittsburgh, PA, United
States.
(4)University of Minnesota, Masonic Comprehensive Cancer Center, Minneapolis,
MN, United States; Division of Biostatistics, School of Public Health,
University of Minnesota, Minneapolis, MN, United States.
(5)University of Minnesota, Tobacco Research Programs, Minneapolis, MN, United
States; University of Minnesota, Family Medicine and Community Health,
Minneapolis, MN, United States.
(6)University of Minnesota, Departments of Family Medicine and Community Health
and Behavioral Sciences, Duluth, MN, United States.
(7)University of Minnesota, Masonic Comprehensive Cancer Center, Minneapolis,
MN, United States; University of Minnesota, Tobacco Research Programs,
Minneapolis, MN, United States; University of Minnesota, Department of
Psychiatry, Minneapolis, MN, United States. Electronic address:
hatsu001@umn.edu.
BACKGROUND: When switching from usual brand cigarettes, very low nicotine
content (VLNC) cigarettes lead to a reduction in the number of cigarettes
smoked, toxicant exposure, withdrawal symptoms and dependence. One area that has
been relatively unexplored is what factors might moderate the effects of VLNC
cigarettes. This exploratory analysis focuses on sex differences in responses to
VLNC cigarettes and nicotine replacement therapy.
METHODS: An exploratory secondary analysis of a randomized trial of 235
participants (58% female, mean age 47 years) comparing a) 0.05-0.09 mg nicotine
yield cigarettes; b) 21 mg nicotine patch and 3) 0.05-0.09 nicotine yield
cigarettes with 21 mg nicotine patch was conducted. We focused on sex
differences in product use, and impact of products on withdrawal response from
usual brand cigarettes and abstinence by randomized group.
RESULTS: The combination of VLNC cigarettes and nicotine patch was more
effective in reducing use of VLNC cigarettes and withdrawal symptoms among males
than females, whereas females were equally responsive to VLNC cigarettes with
and without the nicotine patch. Females were more likely to quit smoking than
males when assigned to either of the conditions that incorporated the VLNC
cigarettes; however, males were more likely to quit smoking in the nicotine
patch alone condition than females.
CONCLUSION: Sex of the smoker may be an important determinant for effects of
VLNC cigarettes and nicotine patch. Future large randomized trials to confirm
these results are needed.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.addbeh.2014.03.021
PMCID: PMC4084708
PMID: 24746485 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest: Dorothy Hatsukami received
funding from Nabi Biopharmaceuticals to conduct a trial on the nicotine vaccine.
No other conflicts of interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/25686106
|
1. Nat Med. 2015 Mar;21(3):263-9. doi: 10.1038/nm.3804. Epub 2015 Feb 16.
The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated
inflammatory disease.
Youm YH(1), Nguyen KY(1), Grant RW(2), Goldberg EL(1), Bodogai M(3), Kim D(4),
D'Agostino D(5), Planavsky N(6), Lupfer C(7), Kanneganti TD(7), Kang S(8),
Horvath TL(1), Fahmy TM(4), Crawford PA(9), Biragyn A(3), Alnemri E(8), Dixit
VD(10).
Author information:
(1)Section of Comparative Medicine and Program on Integrative Cell Signaling and
Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut,
USA.
(2)Department of Nutrition Sciences, Purdue University, West Lafayette, Indiana.
(3)Laboratory of Molecular Biology and Immunology, National Institute on Aging,
National Institutes of Health (NIH), Baltimore, Maryland, USA.
(4)Department of Biomedical Engineering, Yale University, New Haven,
Connecticut, USA.
(5)Department of Molecular Pharmacology and Physiology, University of South
Florida, Tampa, Florida, USA.
(6)Department of Geology and Geophysics, Yale University, New Haven,
Connecticut, USA.
(7)Department of Immunology, St. Jude Children's Hospital, Memphis, Tennessee,
USA.
(8)Department of Biochemistry and Molecular Biology, Thomas Jefferson
University, Philadelphia, Pennsylvania, USA.
(9)Diabetes and Obesity Research Center, Sanford-Burnham Medical Research
Institute, Orlando, Florida, USA.
(10)1] Section of Comparative Medicine and Program on Integrative Cell Signaling
and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut,
USA. [2] Department of Immunobiology, Yale School of Medicine, New Haven,
Connecticut, USA.
Comment in
Nat Rev Immunol. 2015 Apr;15(4):199. doi: 10.1038/nri3832.
Cell Metab. 2015 Apr 7;21(4):513-4. doi: 10.1016/j.cmet.2015.03.012.
Trends Immunol. 2015 Jun;36(6):323-4. doi: 10.1016/j.it.2015.05.001.
The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support
mammalian survival during states of energy deficit by serving as alternative
sources of ATP. BHB levels are elevated by starvation, caloric restriction,
high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged
fasting reduces inflammation; however, the impact that ketones and other
alternative metabolic fuels produced during energy deficits have on the innate
immune response is unknown. We report that BHB, but neither AcAc nor the
structurally related short-chain fatty acids butyrate and acetate, suppresses
activation of the NLRP3 inflammasome in response to urate crystals, ATP and
lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to
pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or
absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical
caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3
inflammasome by preventing K(+) efflux and reducing ASC oligomerization and
speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on
chirality or starvation-regulated mechanisms like AMP-activated protein kinase
(AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB
blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and
independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G
protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB
reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in
human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1
activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such
as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate
crystal-induced peritonitis. Our findings suggest that the anti-inflammatory
effects of caloric restriction or ketogenic diets may be linked to BHB-mediated
inhibition of the NLRP3 inflammasome.
DOI: 10.1038/nm.3804
PMCID: PMC4352123
PMID: 25686106 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18383346
|
1. Glia. 2008 Jul;56(9):975-89. doi: 10.1002/glia.20671.
Modulation of astrocytic metabolic phenotype by proinflammatory cytokines.
Gavillet M(1), Allaman I, Magistretti PJ.
Author information:
(1)Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute,
Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), CH-1015 Switzerland.
Astrocytes play an important role in nervous system homeostasis. In particular,
they contribute to the regulation of local energy metabolism and to oxidative
stress defence. In previous experiments, we showed that long-term treatment with
interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone
increases glucose utilization in primary culture of mouse astrocytes. In our
study, we report that a combination of IL-1beta and TNFalpha exerts a
synergistic effect on glucose utilization and markedly modifies the metabolic
phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a
marked decrease in glycogen levels, a slight but not significant decrease in
lactate release as well as a massive increase in both the pentose phosphate
pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and
lactate release, a typical feature of astrocyte energy metabolism, are altered
after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative
stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha
decreases cellular glutathione content and increases glutathione release into
the extracellular space while stimulating superoxide anion and nitric oxide
production as well as H(2)O(2) release. Interestingly, stimulation of glucose
utilization by IL-1beta+TNFalpha is not affected by the antioxidant
N-acetyl-L-cysteine, suggesting that cellular stress does not account for this
effect. Finally, the effects of cytokines on glucose utilization appear to
involve multiple signaling cascades including the phosphoinositide 3-kinase and
mitogen-activated protein kinases. Taken together these results establish that a
proinflammatory environment such as observed in several neuropathological
conditions including Alzheimer's disease, markedly modifies the metabolic
phenotype of astrocytes.
DOI: 10.1002/glia.20671
PMID: 18383346 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25025523
|
1. Prev Med. 2014 Nov;68:23-8. doi: 10.1016/j.ypmed.2014.07.005. Epub 2014 Jul
13.
Nicotine reduction as an increase in the unit price of cigarettes: a behavioral
economics approach.
Smith TT(1), Sved AF(2), Hatsukami DK(3), Donny EC(4).
Author information:
(1)Department of Psychology, University of Pittsburgh, USA. Electronic address:
tgt4@pitt.edu.
(2)Department of Psychology, University of Pittsburgh, USA; Department of
Neuroscience, University of Pittsburgh, USA.
(3)Department of Psychiatry, University of Minnesota, USA.
(4)Department of Psychology, University of Pittsburgh, USA. Electronic address:
edonny@pitt.edu.
Urgent action is needed to reduce the harm caused by smoking. Product standards
that reduce the addictiveness of cigarettes are now possible both in the U.S.
and in countries party to the Framework Convention on Tobacco Control.
Specifically, standards that required substantially reduced nicotine content in
cigarettes could enable cessation in smokers and prevent future smoking among
current non-smokers. Behavioral economics uses principles from the field of
microeconomics to characterize how consumption of a reinforcer changes as a
function of the unit price of that reinforcer (unit price=cost/reinforcer
magnitude). A nicotine reduction policy might be considered an increase in the
unit price of nicotine because smokers are paying more per unit of nicotine.
This perspective allows principles from behavioral economics to be applied to
nicotine reduction research questions, including how nicotine consumption,
smoking behavior, use of other tobacco products, and use of other drugs of abuse
are likely to be affected. This paper reviews the utility of this approach and
evaluates the notion that a reduction in nicotine content is equivalent to a
reduction in the reinforcement value of smoking-an assumption made by the unit
price approach.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ypmed.2014.07.005
PMCID: PMC4446706
PMID: 25025523 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Dr. Hatsukami was funded by
Nabi Biopharmaceuticals and NIDA to be a site for a nicotine immunotherapy
trial. Tracy Smith, Dr. Sved, and Dr. Donny have no conflicts to report.
|
http://www.ncbi.nlm.nih.gov/pubmed/21232155
|
1. BMC Public Health. 2011 Jan 14;11:37. doi: 10.1186/1471-2458-11-37.
Study protocol for a randomised trial of nicotine-free cigarettes as an adjunct
to usual NRT-based cessation practice, in people who wish to stop smoking.
Walker NK(1), Howe C, Bullen C, Grigg M, Glover M, McRobbie H, Laugesen M,
Vander Hoorn S, Whittaker R.
Author information:
(1)Clinical Trials Research Unit, School of Population Health, The University of
Auckland, Private Bag 92019, Auckland 1142, New Zealand.
n.walker@ctru.auckland.ac.nz
BACKGROUND: Current smoking cessation treatments focus on addressing the
pharmacological dependence of smokers on nicotine. However, new strategies are
needed that address both nicotine dependence and the psychological dependence on
cigarettes as the source of nicotine. Evidence from a number of small smoking
cessation studies suggests that the use of cigarettes with reduced nicotine
content, in combination with nicotine replacement therapy (NRT), may help reduce
withdrawal symptoms and increase quit rates. This paper describes the protocol
for a large randomised-controlled trial to test the effect of using
nicotine-free cigarettes together with NRT on long-term quit rates.
METHODS/DESIGN: This single-blind, randomised trial aims to recruit 1,410
participants through the national telephone-based Quitline service in New
Zealand. Participants in the treatment arm will be asked to stop smoking
nicotine-containing cigarettes on their chosen Quit day and smoke ad libitum
nicotine-free (Quest 3) cigarettes for six weeks. At the same time people in
this group will be asked to start using NRT patches, gum and/or lozenges (as
recommended by Quitline) for eight weeks. Participants in the control arm will
be asked to stop smoking completely on their chosen Quit day and start using NRT
patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Data
collection will occur at baseline, three and six weeks, and three and six months
after Quit day. The primary outcome is the proportion of participants who
self-report seven-day point prevalence abstinence at six months since Quit date.
DISCUSSION: Smoking prevalence in New Zealand has changed little in recent years
(particularly in Māori, the indigenous people of New Zealand) and additional
options for smokers who want to quit are needed. Although a variety of methods
are available to help, many are expensive, have side effects, and despite their
use most quit attempts still fail. This trial will test the balance of benefits
and risks of a new strategy for people to overcome nicotine dependence. Since
smoking is the leading cause of lost healthy life years in New Zealand, if
proven effective this strategy is likely to have substantial public health
benefits.
DOI: 10.1186/1471-2458-11-37
PMCID: PMC3027137
PMID: 21232155 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25798621
|
1. J Clin Invest. 2015 Apr;125(4):1579-90. doi: 10.1172/JCI76468. Epub 2015 Mar
23.
NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage
activation.
Xu J, Chi F, Guo T, Punj V, Lee WN, French SW, Tsukamoto H.
Comment in
Gastroenterology. 2015 Dec;149(7):1979-80. doi:
10.1053/j.gastro.2015.10.012.
Hepatology. 2016 Apr;63(4):1381-3. doi: 10.1002/hep.28386.
Metabolic reprogramming is implicated in macrophage activation, but the
underlying mechanisms are poorly understood. Here, we demonstrate that the
NOTCH1 pathway dictates activation of M1 phenotypes in isolated mouse hepatic
macrophages (HMacs) and in a murine macrophage cell line by coupling
transcriptional upregulation of M1 genes with metabolic upregulation of
mitochondrial oxidative phosphorylation and ROS (mtROS) to augment induction of
M1 genes. Enhanced mitochondrial glucose oxidation was achieved by increased
recruitment of the NOTCH1 intracellular domain (NICD1) to nuclear and
mitochondrial genes that encode respiratory chain components and by
NOTCH-dependent induction of pyruvate dehydrogenase phosphatase 1 (Pdp1)
expression, pyruvate dehydrogenase activity, and glucose flux to the TCA cycle.
As such, inhibition of the NOTCH pathway or Pdp1 knockdown abrogated glucose
oxidation, mtROS, and M1 gene expression. Conditional NOTCH1 deficiency in the
myeloid lineage attenuated HMac M1 activation and inflammation in a murine model
of alcoholic steatohepatitis and markedly reduced lethality following
endotoxin-mediated fulminant hepatitis in mice. In vivo monocyte tracking
further demonstrated the requirement of NOTCH1 for the migration of blood
monocytes into the liver and subsequent M1 differentiation. Together, these
results reveal that NOTCH1 promotes reprogramming of mitochondrial metabolism
for M1 macrophage activation.
DOI: 10.1172/JCI76468
PMCID: PMC4396469
PMID: 25798621 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17573781
|
1. Addict Biol. 2007 Sep;12(3-4):503-12. doi: 10.1111/j.1369-1600.2007.00075.x.
Epub 2007 Jun 16.
Selectively reduced responses to smoking cues in amygdala following
extinction-based smoking cessation: results of a preliminary functional magnetic
resonance imaging study.
McClernon FJ(1), Hiott FB, Liu J, Salley AN, Behm FM, Rose JE.
Author information:
(1)Duke University Medical Center, NC 27708, USA. mccle011@mc.duke.edu
Preliminary studies suggest an extinction-based smoking cessation treatment
using reduced nicotine content (RNC) cigarettes decreases self-report craving
for cigarettes prior to quitting and may be an effective smoking cessation
treatment. The aims of this study was to evaluate the effect of an
extinction-based smoking cessation treatment on brain responses to smoking cues
using blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging
(fMRI). Sixteen (n = 16) dependent smokers were scanned using BOLD fMRI at
baseline, following 2-4 weeks of smoking RNC cigarettes while wearing a 21-mg
nicotine patch, and 2-4 weeks following quitting smoking. During scanning,
participants viewed smoking-related pictures (e.g. lit cigarette) and pictures
of people engaged in everyday activities (e.g. using a stapler). Event-related
BOLD responses to smoking and control cues were analyzed in regions of interest
(ROIs) known to subserve reward, attention, motivation and emotion. The
extinction-based treatment simultaneously attenuated responses to smoking cues
in amygdala while potentiating responses to control cues. Exploratory analysis
indicated that this pattern was also observed in the thalamus of future
abstinent but not relapsing smokers. The results of this preliminary study
suggest that an extinction-based treatment for smoking cessation alters brain
responses to smoking and control cues in amygdala--a region previously
associated with drug cue reactivity and extinction.
DOI: 10.1111/j.1369-1600.2007.00075.x
PMID: 17573781 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23603206
|
1. Cancer Epidemiol Biomarkers Prev. 2013 Jun;22(6):1015-24. doi:
10.1158/1055-9965.EPI-12-1439. Epub 2013 Apr 19.
Reduced nicotine content cigarettes and nicotine patch.
Hatsukami DK(1), Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS,
Carmella SG, al'Absi M, Joseph AM, Allen SS.
Author information:
(1)Tobacco Research, University of Minnesota, Minneapolis, MN 55414, USA.
hatsu001@umn.edu
BACKGROUND: Reduced nicotine content (RNC) cigarettes have led to smoking fewer
cigarettes, withdrawal relief, and facilitation of cessation. The aim of this
study is to examine the effects RNC cigarettes with and without nicotine patch
and patch alone on smoking behavior, toxicant exposure, withdrawal discomfort,
and as an exploratory analysis, on long-term abstinence.
METHODS: This study involved a randomized, parallel arm design and six weeks of:
(i) 0.05-0.09 mg nicotine yield cigarettes (N = 79); (ii) 21 mg nicotine patch
(N = 80), or (iii) 0.05-0.09 nicotine yield cigarettes with 21 mg nicotine patch
(N = 76); all groups received six weeks of additional behavioral treatment with
follow-ups up to six months.
RESULTS: Combination approach led to lower rates of smoking assigned cigarettes
and hence lower carbon monoxide levels than RNC cigarettes alone. In addition,
the combination approach was associated with less withdrawal severity when
switching from usual brand to assigned product, and less smoking of usual brand
cigarettes during treatment, but not after treatment compared with the other
approaches.
CONCLUSION: Combining very low nicotine content cigarettes with nicotine patch
may improve the acute effects resulting from switching to either of these
products alone.
IMPACT: These findings may have implications for smoking cessation treatment or
a policy measure to reduce nicotine content in cigarettes.
DOI: 10.1158/1055-9965.EPI-12-1439
PMCID: PMC3681886
PMID: 23603206 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24175256
|
1. World J Nephrol. 2012 Dec 6;1(6):166-76. doi: 10.5527/wjn.v1.i6.166.
Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic
kidney disease.
Canavesi E(1), Alfieri C, Pelusi S, Valenti L.
Author information:
(1)Elena Canavesi, Serena Pelusi, Luca Valenti, Internal Medicine, Department of
Pathophysiology and Transplantation, Università degli Studi di Milano,
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F Sforza 35,
20122 Milano, Italy.
The anemia of chronic kidney disease and hemodialysis is characterized by
chronic inflammation and release of cytokines, resulting in the upregulation of
the iron hormone hepcidin, also increased by iron therapy and reduced glomerular
filtration, with consequent reduction in iron absorption, recycling, and
availability to the erythron. This response proves advantageous in the
short-term to restrain iron availability to pathogens, but ultimately leads to
severe anemia, and impairs the response to erythropoietin (Epo) and iron.
Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron
metabolism by hampering hepcidin release by hepatocytes in response to increased
iron stores, thereby resulting in inadequate inhibition of the activity of
Ferroportin-1, inappropriately high iron absorption and recycling, and iron
overload. However, in hemodialysis patients, carriage of HFE mutations may
confer an adaptive benefit by decreasing hepcidin release in response to iron
infusion and inflammation, thereby improving iron availability to
erythropoiesis, anemia control, the response to Epo, and possibly survival.
Therefore, anti-hepcidin therapies may improve anemia management in
hemodialysis. However, HFE mutations directly favor hemoglobinization
independently of hepcidin, and reduce macrophages activation in response to
inflammation, whereas hepcidin might also play a beneficial anti-inflammatory
and anti-microbic action during sepsis, so that direct inhibition of
HFE-mediated regulation of iron metabolism may represent a valuable alternative
therapeutic target. Genetic studies may offer a valuable tool to test these
hypotheses and guide the research of new therapies.
DOI: 10.5527/wjn.v1.i6.166
PMCID: PMC3782218
PMID: 24175256
|
http://www.ncbi.nlm.nih.gov/pubmed/18629723
|
1. Nicotine Tob Res. 2008 Jul;10(7):1139-48. doi: 10.1080/14622200802123294.
A randomized trial of nicotine replacement therapy in combination with
reduced-nicotine cigarettes for smoking cessation.
Becker KM(1), Rose JE, Albino AP.
Author information:
(1)Becker & Associates Consulting, Inc., Washington, DC, USA.
A randomized double-blind, active controlled, parallel group, multi-center phase
II clinical trial was conducted to evaluate the efficacy of reduced-nicotine
cigarettes as a novel smoking cessation treatment (under Investigational Device
Exemption 69,185). The concept for a reduced-nicotine cigarette designed to
progressively wean smokers from the smoking habit is based on research
demonstrating that successful smoking cessation is not only dependent on
withdrawal of nicotine, but also on weaning from the habitual sensory and
behavioral reinforcement of smoking. Treatment consisted of Quest brand of
cigarettes (Quest 1, 2, and 3), which respectively deliver 0.59+/-0.06,
0.3+/-0.05, and less than 0.05 mg nicotine, either alone or in combination with
nicotine replacement therapy (NRT). The primary endpoint was 4 weeks of
continuous abstinence (Weeks 7-10), with additional follow-up at 3 and 6 months.
Adult men and women smokers (N = 346), motivated to quit, were randomized to one
of three treatment groups: Quest plus NRT (NRT pretreatment 2 weeks before, and
NRT after the quit date), Quest plus placebo patch, or active control plus NRT
(conventional cigarette, followed by NRT after quit date). Results showed that
Quest plus NRT was more effective than active control plus NRT in achieving 4
weeks of continuous abstinence (32.8% vs. 21.9%). Quest plus placebo patch
yielded an abstinence rate similar to that of the active control plus NRT (16.4%
vs. 21.9%). No serious adverse events were attributable to the investigational
product. Quest plus NRT offers promise as a new smoking cessation treatment.
DOI: 10.1080/14622200802123294
PMID: 18629723 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20078491
|
1. Addiction. 2010 Feb;105(2):343-55. doi: 10.1111/j.1360-0443.2009.02780.x.
Reduced nicotine content cigarettes: effects on toxicant exposure, dependence
and cessation.
Hatsukami DK(1), Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen JA,
Allen SS, Shields PG, Murphy SE, Stepanov I, Hecht SS.
Author information:
(1)University of Minnesota Transdisciplinary Tobacco Use Research Center,
Minneapolis, MN 55414, USA. hatsu001@umn.edu
Comment in
Addiction. 2010 Feb;105(2):356-7. doi: 10.1111/j.1360-0443.2009.02882.x.
AIMS: To examine the effects of reduced nicotine cigarettes on smoking behavior,
toxicant exposure, dependence and abstinence.
DESIGN: Randomized, parallel arm, semi-blinded study. Setting University of
Minnesota Tobacco Use Research Center.
INTERVENTIONS: Six weeks of: (i) 0.05 mg nicotine yield cigarettes; (ii) 0.3 mg
nicotine yield cigarettes; or (iii) 4 mg nicotine lozenge; 6 weeks of follow-up.
Measurements Compensatory smoking behavior, biomarkers of exposure, tobacco
dependence, tobacco withdrawal and abstinence rate.
FINDINGS: Unlike the 0.3 mg cigarettes, 0.05 mg cigarettes were not associated
with compensatory smoking behaviors. Furthermore, the 0.05 mg cigarettes and
nicotine lozenge were associated with reduced carcinogen exposure, nicotine
dependence and product withdrawal scores. The 0.05 mg cigarette was associated
with greater relief of withdrawal from usual brand cigarettes than the nicotine
lozenge. The 0.05 mg cigarette led to a significantly higher rate of cessation
than the 0.3 mg cigarette and a similar rate as nicotine lozenge.
CONCLUSION: The 0.05 mg nicotine yield cigarettes may be a tobacco product that
can facilitate cessation; however, future research is clearly needed to support
these preliminary findings.
DOI: 10.1111/j.1360-0443.2009.02780.x
PMCID: PMC4565618
PMID: 20078491 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24159166
|
1. Blood. 2013 Oct 24;122(17):2929-31. doi: 10.1182/blood-2013-08-522466.
Anti-hepcidin therapy for iron-restricted anemias.
Nemeth E(1).
Author information:
(1)UNIVERSITY OF CALIFORNIA, LOS ANGELES.
Comment on
Blood. 2013 Oct 24;122(17):3054-61. doi: 10.1182/blood-2013-06-505792.
In this issue of Blood, Cooke et al demonstrate the potential of a fully human
anti-hepcidin antibody as a novel therapeutic for iron-restricted anemias such
as anemia of inflammation, cancer, or chronic kidney disease (formerly known as
“anemia of chronic diseases”).
DOI: 10.1182/blood-2013-08-522466
PMCID: PMC8940288
PMID: 24159166 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: E.N. is a
stockholder and consultant for Intrinsic LifeSciences, a biotech company
developing hepcidin diagnostics, and Merganser Biotech, a biotech company
developing hepcidin therapeutics.
|
http://www.ncbi.nlm.nih.gov/pubmed/24231125
|
1. Clin Chem Lab Med. 2014 May;52(5):613-9. doi: 10.1515/cclm-2013-0769.
Hepcidin levels in chronic hemodialysis patients: a critical evaluation.
Valenti L, Messa P, Pelusi S, Campostrini N, Girelli D.
Altered systemic iron metabolism is a key element of uremia, and functional iron
deficiency mainly related to subclinical inflammation makes it difficult to
maintain proper control of anemia in chronic hemodialysis patients (CHD). In the
last decade, the hepatic hormone hepcidin has been progressively recognized as
the master regulator of circulating iron levels through the modulation of
cellular iron fluxes in response to iron stores, as well as to erythroid and
inflammatory stimuli. Hepcidin is cleared by the kidney and progression of renal
disease has been associated to increased serum hepcidin levels. This, in turn,
reduces iron availability for erythropoiesis, suggesting anti-hepcidin
strategies for improving anemia control. Moreover, hepcidin has been recently
implicated in the pathogenesis of long-term complications of dialysis, like
accelerated atherosclerosis. Initial studies almost invariably reported a
sustained increase of serum hepcidin in chronic hemodialysis patients.
Noteworthy, such studies included relatively few patients and controls that were
poorly matched for major determinants of serum hepcidin at population level,
i.e., age and gender. More recent data based on accurately matched larger series
challenge the view that hepcidin is intrinsically increased in hemodialysis
patients, showing a marked inter- and intra-individual variability of hormone
levels. Here we take a critical look to the data published so far on hepcidin
levels in CHD, analyze the reasons underlying the discrepancies in available
studies and the hepcidin variability in CHD, and point out the need for further
studies in large series of well-characterized CHD patients and controls.
DOI: 10.1515/cclm-2013-0769
PMID: 24231125 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19793786
|
1. Nicotine Tob Res. 2009 Nov;11(11):1274-9. doi: 10.1093/ntr/ntp147. Epub 2009
Sep 30.
Reduced-nicotine content cigarettes: Is there potential to aid smoking
cessation?
Walker N(1), Bullen C, McRobbie H.
Author information:
(1)Clinical Trials Research Unit, School of Population Health, University of
Auckland, Private Bag 92019, Auckland 1072, New Zealand.
n.walker@ctru.auckland.ac.nz
INTRODUCTION: Current smoking cessation treatments largely address
pharmacological dependence on nicotine. New approaches are needed that address
both nicotine dependence and psychological dependence on cigarettes as the
source of nicotine. One such approach is the use of cigarettes with reduced
nicotine content.
METHODS: We reviewed the available literature on the use of reduced-nicotine
content cigarettes as a cessation aid.
RESULTS: One case series study and trial data indicate that reduction in the
level of nicotine in cigarette tobacco can reduce the level of nicotine
dependence in smokers and do so without adverse effects on cardiovascular
biomarkers or significant compensatory smoking. We identified three clinical
trials (total n = 489) that suggest that smokers can dissociate nicotine
delivery from the act of smoking if they use reduced-nicotine content cigarettes
in combination with nicotine replacement therapy.
DISCUSSION: The identified studies point to a benefit but involved only a small
number of participants and provide only limited data on long-term abstinence.
More definitive evidence from larger trials with longer follow-up is needed to
clarify the role of reduced nicotine cigarettes as an aid to smoking cessation.
DOI: 10.1093/ntr/ntp147
PMID: 19793786 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24086109
|
1. PLoS Biol. 2013 Sep;11(9):e1001665. doi: 10.1371/journal.pbio.1001665. Epub
2013 Sep 24.
HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the
alveolar epithelium.
Eckle T(1), Brodsky K, Bonney M, Packard T, Han J, Borchers CH, Mariani TJ,
Kominsky DJ, Mittelbronn M, Eltzschig HK.
Author information:
(1)Organ Protection Program, Department of Anesthesiology, University of
Colorado School of Medicine, Denver, Colorado, United States of America.
Comment in
PLoS Biol. 2013 Sep;11(9):e1001664. doi: 10.1371/journal.pbio.1001664.
BACKGROUND: While acute lung injury (ALI) contributes significantly to critical
illness, it resolves spontaneously in many instances. The majority of patients
experiencing ALI require mechanical ventilation. Therefore, we hypothesized that
mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia
could activate endogenous pathways important in lung protection.
METHODS AND FINDINGS: To examine transcriptional responses during ALI, we
exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro
model resembling mechanical ventilation. A genome-wide screen revealed a
transcriptional response similar to hypoxia signaling. Surprisingly, we found
that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch
conditions in vitro or during ventilator-induced ALI in vivo occurs under
normoxic conditions. Extension of these findings identified a functional role
for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating
normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and
improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF
activator or inhibitor treatment implicated HIF1A-stabilization in attenuating
pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of
HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked
these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose
metabolites utilizing liquid-chromatography tandem mass-spectrometry
demonstrated that increases in glycolytic capacity, improvement of mitochondrial
respiration, and concomitant attenuation of lung inflammation during ALI were
specific for alveolar-epithelial expressed HIF1A.
CONCLUSIONS: These studies reveal a surprising role for HIF1A in lung protection
during ALI, where normoxic HIF1A stabilization and HIF-dependent control of
alveolar-epithelial glucose metabolism function as an endogenous feedback loop
to dampen lung inflammation.
DOI: 10.1371/journal.pbio.1001665
PMCID: PMC3782424
PMID: 24086109 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/25461442
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1. PLoS One. 2014 Dec 2;9(12):e113860. doi: 10.1371/journal.pone.0113860.
eCollection 2014.
Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple
dysregulated pathways.
Rachakonda V(1), Gabbert C(1), Raina A(1), Bell LN(2), Cooper S(3), Malik S(1),
Behari J(1).
Author information:
(1)Department of Medicine, Divisions of Gastroenterology, Hepatology, and
Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of
America.
(2)Metabolon, Inc., Durham, North Carolina, United States of America.
(3)Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, United States
of America.
BACKGROUND AND OBJECTIVES: While animal studies have implicated derangements of
global energy homeostasis in the pathogenesis of acute alcoholic hepatitis
(AAH), the relevance of these findings to the development of human AAH remains
unclear. Using global, unbiased serum metabolomics analysis, we sought to
characterize alterations in metabolic pathways associated with severe AAH and
identify potential biomarkers for disease prognosis.
METHODS: This prospective, case-control study design included 25 patients with
severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples
were collected within 24 hours of the index clinical encounter. Global, unbiased
metabolomics profiling was performed. Patients were followed for 180 days after
enrollment to determine survival.
RESULTS: Levels of 234 biochemicals were altered in subjects with severe AAH.
Random-forest analysis, principal component analysis, and integrated
hierarchical clustering methods demonstrated that metabolomics profiles
separated the two cohorts with 100% accuracy. Severe AAH was associated with
enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta
oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids
and related metabolites suggested decreased plasma membrane remodeling in severe
AAH. While most measured bile acids were increased in severe AAH, low
deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis.
Several changes in substrate utilization for energy homeostasis were identified
in severe AAH, including increased glucose consumption by the pentose phosphate
pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide
catabolism. Finally, altered levels of small molecules related to glutathione
metabolism and antioxidant vitamin depletion were observed in patients with
severe AAH. Univariable logistic regression revealed 15 metabolites associated
with 180-day survival in severe AAH.
CONCLUSION: Severe AAH is characterized by a distinct metabolic phenotype
spanning multiple pathways. Metabolomics profiling revealed a panel of
biomarkers for disease prognosis, and future studies are planned to validate
these findings in larger cohorts of patients with severe AAH.
DOI: 10.1371/journal.pone.0113860
PMCID: PMC4252257
PMID: 25461442 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Dr. Lauren N. Bell is an
employee of Metabolon, Inc. and, as such, has affiliations with or financial
involvement with Metabolon, Inc. She has no other relevant affiliations or
financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed. This does not alter the authors'
adherence to PLOS ONE policies on sharing data and materials.
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http://www.ncbi.nlm.nih.gov/pubmed/21287666
|
1. Inflamm Bowel Dis. 2011 Nov;17(11):2261-74. doi: 10.1002/ibd.21616. Epub 2011
Feb 1.
GCMS-based metabolomic study in mice with colitis induced by dextran sulfate
sodium.
Shiomi Y(1), Nishiumi S, Ooi M, Hatano N, Shinohara M, Yoshie T, Kondo Y,
Furumatsu K, Shiomi H, Kutsumi H, Azuma T, Yoshida M.
Author information:
(1)Division of Gastroenterology, Department of Internal Medicine, Graduate
School of Medicine, Kobe University, Kobe, Japan.
BACKGROUND: Metabolomics provides data about all the metabolic processes of a
cell or organism. So far, the changes that occur in the levels of metabolites
during the development of colitis have not been fully elucidated. Here we
examined the changes of metabolite levels in the serum and colon tissue of
colitis mice using gas chromatography mass spectrometry (GC/MS) with the aim of
achieving a detailed understanding of the pathogenesis of inflammatory bowel
disease (IBD).
METHODS: To induce colitis, C57BL/6J mice were administered 3.0% dextran sulfate
sodium (DSS) in their drinking water for 5 days and were subsequently given
drinking water alone.
RESULTS: A total of 77 and 92 metabolites were detected in serum and colon
tissue, respectively, and among the metabolites the compositions of TCA cycle
intermediates and amino acids changed depending on the degree of colitis. Then,
partial least square discriminant analysis (PLS-DA), a multiple classification
analysis, showed distinct clustering and clear separation of the groups
according to the degree of colitis. Furthermore, PLS-DA loadings plots revealed
that succinic acid, indole-3-acetic acid, glutamic acid, and glutamine were the
main contributors to the separation of each stage of colitis. In addition, it
was revealed that supplementation with glutamine, the level of which was
significantly decreased in the acute phase of colonic inflammation, attenuated
colitis induced by DSS.
CONCLUSIONS: Our results suggest that metabolomics is capable of representing
the various degrees of colitis, and our findings will aid in the discovery of
therapeutic agents for IBD and other inflammatory disorders by metabolomic
approaches.
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
DOI: 10.1002/ibd.21616
PMID: 21287666 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/19555498
|
1. Theor Biol Med Model. 2009 Jun 25;6:9. doi: 10.1186/1742-4682-6-9.
Theoretical study of the Usutu virus helicase 3D structure, by means of
computer-aided homology modelling.
Vlachakis D(1).
Author information:
(1)Institute of Biology, National Centre for Scientific Research Demokritos,
Paraskevi Attikis, Greece. dimitris@bio.demokritos.gr
BACKGROUND: Usutu virus belongs to the Flaviviridae viral family and constitutes
an important pathogen. The viral helicase is an ideal target for inhibitor
design, since this enzyme is essential for the survival, proliferation and
transmission of the virus.
RESULTS: Towards a drug-design approach, the 3D model of the Usutu virus
helicase structure has been designed, using conventional homology modelling
techniques and the known 3D-structure of the Murray Valley Encephalitis virus
helicase, of the same viral family, as template. The model was then subjected to
extended molecular dynamics simulations in a periodic box, filled with explicit
water molecules for 10 nanoseconds. The reliability of the model was confirmed
by obtaining acceptable scores from a variety of in silico scoring tools,
including Procheck and Verify3D.
CONCLUSION: [corrected] The 3D model of the Usutu virus helicase exhibits in
silico all known structural characteristics of the Flaviviridae viral family
helicase enzymes and could provide the platform for further de novo
structure-based design of novel anti-Usutu agents.
DOI: 10.1186/1742-4682-6-9
PMCID: PMC2707372
PMID: 19555498 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21249176
|
1. PLoS Pathog. 2011 Jan 13;7(1):e1001255. doi: 10.1371/journal.ppat.1001255.
Identification and characterization of the host protein DNAJC14 as a broadly
active flavivirus replication modulator.
Yi Z(1), Sperzel L, Nürnberger C, Bredenbeek PJ, Lubick KJ, Best SM, Stoyanov
CT, Law LM, Yuan Z, Rice CM, MacDonald MR.
Author information:
(1)Laboratory of Virology and Infectious Disease, The Rockefeller University,
New York, New York, USA.
Viruses in the Flavivirus genus of the Flaviviridae family are
arthropod-transmitted and contribute to staggering numbers of human infections
and significant deaths annually across the globe. To identify cellular factors
with antiviral activity against flaviviruses, we screened a cDNA library using
an iterative approach. We identified a mammalian Hsp40 chaperone protein
(DNAJC14) that when overexpressed was able to mediate protection from yellow
fever virus (YFV)-induced cell death. Further studies revealed that DNAJC14
inhibits YFV at the step of viral RNA replication. Since replication of bovine
viral diarrhea virus (BVDV), a member of the related Pestivirus genus, is also
known to be modulated by DNAJC14, we tested the effect of this host factor on
diverse Flaviviridae family members. Flaviviruses, including the pathogenic
Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a
Hepacivirus, hepatitis C virus (HCV), all were inhibited by overexpression of
DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain,
which mediates self-interaction, are required for anti-YFV activity. We found
that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory
mutants demonstrate that DNAJC14 is recruited to YFV replication complexes.
Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges
during infection and is found in replication complexes identified by dsRNA
staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV
replication suggesting a requirement for DNAJC14 in YFV replication complex
assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a
time- and dose-dependent manner. DNAJC14 overexpression may disrupt the proper
stoichiometry resulting in inhibition, which can be overcome upon restoration of
the optimal ratios due to the accumulation of viral nonstructural proteins. Our
findings, together with previously published work, suggest that the members of
the Flaviviridae family have evolved in unique and important ways to interact
with this host Hsp40 chaperone molecule.
DOI: 10.1371/journal.ppat.1001255
PMCID: PMC3020928
PMID: 21249176 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/25281749
|
1. Otolaryngol Head Neck Surg. 2015 Jan;152(1):57-62. doi:
10.1177/0194599814552065. Epub 2014 Oct 3.
Computer aided-designed, 3-dimensionally printed porous tissue bioscaffolds for
craniofacial soft tissue reconstruction.
Zopf DA(1), Mitsak AG(2), Flanagan CL(2), Wheeler M(3), Green GE(1), Hollister
SJ(4).
Author information:
(1)Department of Otolaryngology-Head and Neck Surgery, University of Michigan,
Ann Arbor, Ann Arbor, Michigan, USA.
(2)Departments of Biomedical Engineering, Mechanical Engineering, and Surgery,
University of Michigan, Ann Arbor, Ann Arbor, Michigan, USA.
(3)Institute for Genomic Biology, Department of Animal Sciences, University of
Illinois at Urbana-Champaign, Urbana-Champaign, Illinois, USA.
(4)Departments of Biomedical Engineering, Mechanical Engineering, and Surgery,
University of Michigan, Ann Arbor, Ann Arbor, Michigan, USA scottho@umich.edu.
OBJECTIVE: To determine the potential of an integrated, image-based
computer-aided design (CAD) and 3-dimensional (3D) printing approach to engineer
scaffolds for head and neck cartilaginous reconstruction for auricular and nasal
reconstruction.
STUDY DESIGN: Proof of concept revealing novel methods for bioscaffold
production with in vitro and in vivo animal data.
SETTING: Multidisciplinary effort encompassing 2 academic institutions.
SUBJECTS AND METHODS: Digital Imaging and Communications in Medicine (DICOM)
computed tomography scans were segmented and utilized in image-based CAD to
create porous, anatomic structures. Bioresorbable polycaprolactone scaffolds
with spherical and random porous architecture were produced using a laser-based
3D printing process. Subcutaneous in vivo implantation of auricular and nasal
scaffolds was performed in a porcine model. Auricular scaffolds were seeded with
chondrogenic growth factors in a hyaluronic acid/collagen hydrogel and cultured
in vitro over 2 months' duration.
RESULTS: Auricular and nasal constructs with several types of microporous
architecture were rapidly manufactured with high fidelity to human patient
anatomy. Subcutaneous in vivo implantation of auricular and nasal scaffolds
resulted in an excellent appearance and complete soft tissue ingrowth.
Histological analysis of in vitro scaffolds demonstrated native-appearing
cartilaginous growth that respected the boundaries of the scaffold.
CONCLUSION: Integrated, image-based CAD and 3D printing processes generated
patient-specific nasal and auricular scaffolds that supported cartilage
regeneration.
© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.
DOI: 10.1177/0194599814552065
PMCID: PMC4760858
PMID: 25281749 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12679063
|
1. Trends Biotechnol. 2003 Apr;21(4):157-61. doi: 10.1016/S0167-7799(03)00033-7.
Organ printing: computer-aided jet-based 3D tissue engineering.
Mironov V(1), Boland T, Trusk T, Forgacs G, Markwald RR.
Author information:
(1)Department of Cell Biology and Anatomy, Medical University of South Carolina,
Charleston, SC 29425, USA. mironovv@musc.edu
Erratum in
Trends Biotechnol. 2004 Jun;22(6):265.
Tissue engineering technology promises to solve the organ transplantation
crisis. However, assembly of vascularized 3D soft organs remains a big
challenge. Organ printing, which we define as computer-aided, jet-based 3D
tissue-engineering of living human organs, offers a possible solution. Organ
printing involves three sequential steps: pre-processing or development of
"blueprints" for organs; processing or actual organ printing; and postprocessing
or organ conditioning and accelerated organ maturation. A cell printer that can
print gels, single cells and cell aggregates has been developed. Layer-by-layer
sequentially placed and solidified thin layers of a thermo-reversible gel could
serve as "printing paper". Combination of an engineering approach with the
developmental biology concept of embryonic tissue fluidity enables the creation
of a new rapid prototyping 3D organ printing technology, which will dramatically
accelerate and optimize tissue and organ assembly.
DOI: 10.1016/S0167-7799(03)00033-7
PMID: 12679063 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23945733
|
1. Reprod Sci. 2013 Oct;20(10):1130-6. doi: 10.1177/1933719113497290. Epub 2013
Aug 13.
Profile of ospemifene in the breast.
Berga SL(1).
Author information:
(1)Department of Obstetrics and Gynecology, Wake Forest School of Medicine,
Winston-Salem, NC, USA. sberga@wakehealth.edu
Vulvar and vaginal atrophy (VVA) is a chronic, progressive medical condition
prevalent among postmenopausal women, which produces symptoms such as
dyspareunia, vaginal dryness, and vaginal irritation. Currently, the only
prescription options are systemic and vaginal estrogen therapies that may be
limited by concerns about long-term safety and breast cancer risk. Ospemifene is
a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor
modulator) recently approved by the US Food and Drug Administration for
treatment of dyspareunia, a symptom of VVA, due to menopause. Ospemifene, the
first nonestrogen oral treatment for this indication, may provide an alternative
to treatment with estrogen. Animal models with ospemifene suggest an inhibitory
effect on growth of malignant breast tissue, but animal data cannot necessarily
be extrapolated to humans. Clinical trials, including 3 long-term studies
assessing the overall safety of ospemifene, support that ospemifene is generally
well tolerated, with beneficial effects on the vagina, neutral effects on the
breast, and minimal effects on the endometrium.
DOI: 10.1177/1933719113497290
PMID: 23945733 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24805923
|
1. Nat Commun. 2014 May 8;5:3774. doi: 10.1038/ncomms4774.
Bio-inspired detoxification using 3D-printed hydrogel nanocomposites.
Gou M(1), Qu X(2), Zhu W(3), Xiang M(4), Yang J(5), Zhang K(6), Wei Y(4), Chen
S(7).
Author information:
(1)1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital,
West China Medical School, Sichuan University, Chengdu 610041, P.R. China [2]
Shiley Eye Center and Institute for Genomic Medicine, University of California,
San Diego, La Jolla, California 92093, USA [3].
(2)1] Department of NanoEngineering, University of California, San Diego, La
Jolla, California 92093, USA [2].
(3)Department of NanoEngineering, University of California, San Diego, La Jolla,
California 92093, USA.
(4)State Key Laboratory of Biotherapy and Cancer Center, West China Hospital,
West China Medical School, Sichuan University, Chengdu 610041, P.R. China.
(5)School of Chemistry and Chemical Engineering, Shaanxi Normal University,
Xi'an 710062, P.R. China.
(6)1] Shiley Eye Center and Institute for Genomic Medicine, University of
California, San Diego, La Jolla, California 92093, USA [2] Biomaterials and
Tissue Engineering Center, University of California, San Diego, La Jolla,
California 92093, USA [3] Veterans Administration Healthcare System, San Diego,
California 92093, USA.
(7)1] Department of NanoEngineering, University of California, San Diego, La
Jolla, California 92093, USA [2] Biomaterials and Tissue Engineering Center,
University of California, San Diego, La Jolla, California 92093, USA.
Rationally designed nanoparticles that can bind toxins show great promise for
detoxification. However, the conventional intravenous administration of
nanoparticles for detoxification often leads to nanoparticle accumulation in the
liver, posing a risk of secondary poisoning especially in liver-failure
patients. Here we present a liver-inspired three-dimensional (3D) detoxification
device. This device is created by 3D printing of designer hydrogels with
functional polydiacetylene nanoparticles installed in the hydrogel matrix. The
nanoparticles can attract, capture and sense toxins, while the 3D matrix with a
modified liver lobule microstructure allows toxins to be trapped efficiently.
Our results show that the toxin solution completely loses its virulence after
treatment using this biomimetic detoxification device. This work provides a
proof-of-concept of detoxification by a 3D-printed biomimetic nanocomposite
construct in hydrogel, and could lead to the development of alternative
detoxification platforms.
DOI: 10.1038/ncomms4774
PMCID: PMC4024742
PMID: 24805923 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24523458
|
1. Development. 2014 Mar;141(6):1197-208. doi: 10.1242/dev.101915. Epub 2014 Feb
12.
Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ
homeostasis and maintenance of axial patterning.
Lin AY(1), Pearson BJ.
Author information:
(1)The Hospital for Sick Children, Program in Developmental and Stem Cell
Biology, Toronto, ON M5G 1X8, Canada.
During adult homeostasis and regeneration, the freshwater planarian must
accomplish a constant balance between cell proliferation and cell death, while
also maintaining proper tissue and organ size and patterning. How these ordered
processes are precisely modulated remains relatively unknown. Here we show that
planarians use the downstream effector of the Hippo signaling cascade, yorkie
(yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in
organ homeostasis, stem cell regulation, regeneration and axial patterning. We
show that yki functions to maintain the homeostasis of the planarian excretory
(protonephridial) system and to limit stem cell proliferation, but does not
affect the differentiation process or cell death. Finally, we show that Yki acts
synergistically with WNT/β-catenin signaling to repress head determination by
limiting the expression domains of posterior WNT genes and that of the
WNT-inhibitor notum. Together, our data show that yki is a key gene in
planarians that integrates stem cell proliferation control, organ homeostasis,
and the spatial patterning of tissues.
DOI: 10.1242/dev.101915
PMID: 24523458 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25492194
|
1. Mater Sci Eng C Mater Biol Appl. 2015 Feb;47:237-47. doi:
10.1016/j.msec.2014.11.024. Epub 2014 Nov 8.
3D printing of porous hydroxyapatite scaffolds intended for use in bone tissue
engineering applications.
Cox SC(1), Thornby JA(1), Gibbons GJ(2), Williams MA(1), Mallick KK(1).
Author information:
(1)WMG, University of Warwick, Coventry CV4 7AL, UK.
(2)WMG, University of Warwick, Coventry CV4 7AL, UK. Electronic address:
G.J.Gibbons@warwick.ac.uk.
A systematic characterisation of bone tissue scaffolds fabricated via 3D
printing from hydroxyapatite (HA) and poly(vinyl)alcohol (PVOH) composite
powders is presented. Flowability of HA:PVOH precursor materials was observed to
affect mechanical stability, microstructure and porosity of 3D printed
scaffolds. Anisotropic behaviour of constructs and part failure at the
boundaries of interlayer bonds was highlighted by compressive strength testing.
A trade-off between the ability to facilitate removal of PVOH thermal
degradation products during sintering and the compressive strength of green
parts was revealed. The ultimate compressive strength of 55% porous green
scaffolds printed along the Y-axis and dried in a vacuum oven for 6h was 0.88 ±
0.02 MPa. Critically, the pores of 3D printed constructs could be user designed,
ensuring bulk interconnectivity, and the imperfect packing of powder particles
created an inherent surface roughness and non-designed porosity within the
scaffold. These features are considered promising since they are known to
facilitate osteoconduction and osteointegration in-vivo. Characterisation
techniques utilised in this study include two funnel flow tests, scanning
electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR),
compressive strength testing and computed tomography (CT).
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.msec.2014.11.024
PMID: 25492194 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2087655
|
1. Ultraschall Med. 1990 Dec;11(6):295-301. doi: 10.1055/s-2007-1011580.
[3-dimensional organ image using ultrasound].
[Article in German]
Sohn C(1), Grotepass J.
Author information:
(1)Abteilung Angiologie, Universitätsklinik Essen.
This is the first report in literature on three-dimensional imaging of organs
via sonography. The relevant experiments were performed in vitro. Whereas MRI
and CT can produce three-dimensional images of bodies by means of appropriate
computer programmes, we had to search for special techniques in sonography that
would communicate to the computer the exact positioning and arrangement of the
individual segments to be reconstructed to supply a three-dimensional image. In
MRI and CT the individual segments are arranged parallel to one another; the
distance between the individual segments is known; all the computer has to do is
to add up these segments to produce a spatial image. In contrast to this,
conventional sonography cannot supply parallel segments or sections due to the
unevenness of the human skin. Hence, it was not possible to use the computer
programmes compiled for the three-dimensional reconstruction of MRI and CT
images, in sonography; special transducer guides had to be constructed before
this could be realised. One of our special constructions enabled parallel
shifting of the transducer to obtain parallel segments or sections, and another
construction enabled rotation of the transducer to obtain segments or sections
differing from one another by a known angle of displacement. In this manner the
computer was able to reconstruct an organ to supply a three-dimensional image--a
first-time achievement. Using these devices, we examined a kidney in a
water-bath. By means of outlining of the individual sonographic segments, only
their surfaces are depicted, and these are reconstructed to produce a
three-dimensional body by means of newly developed computer programmes.(ABSTRACT
TRUNCATED AT 250 WORDS)
DOI: 10.1055/s-2007-1011580
PMID: 2087655 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24055829
|
1. Steroids. 2013 Dec 11;78(12-13):1273-80. doi: 10.1016/j.steroids.2013.09.003.
Epub 2013 Sep 18.
Tissue selectivity of ospemifene: pharmacologic profile and clinical
implications.
Kangas L(1), Unkila M.
Author information:
(1)Hormos Medical Ltd, Turku, Finland. Electronic address:
lauri.kangas@forendo.com.
The multifactorial consequences of menopausal estrogen deficiency affect
numerous tissues throughout the body. Supplemental hormonal therapies carry the
burden of a risk/benefit ratio that must be highly individualized. Selective
estrogen receptor modulators (SERMs) are estrogen receptor (ER)
agonist/antagonists designed to induce benefits comparable with estrogen while
minimizing adverse effects. Here, we review the estrogen agonist/antagonist
profile of ospemifene, a novel triphenylethylene derivative recently approved to
treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to
menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with
approximately equal affinities. In preclinical models, ospemifene increased
vaginal and uterine epithelial thickness and mucification to the same extent as
estrogen. Ospemifene did not induce endometrial hyperplasia in animal models;
there also was no stimulatory effect on endometrial cells. In rat and human
mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on
estrogen-induced cell responses and cell proliferation, supporting an
antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic
effect on bone, as seen by improved bone mineral density, strength, mass, and
histomorphometry in preclinical models, consistent with improvements in markers
of bone resorption and formation in postmenopausal women. Based on the
preclinical evidence, ospemifene has beneficial estrogen-like effects on the
vaginal epithelium, preliminary evidence to support a neutral endometrial
profile, antiproliferative effects in breast, and estrogenic effects in bone.
Taken together, especially regarding estrogen-like effects on the vaginal
epithelium, ospemifene presents a profile of tissue-specific effects that appear
novel among available SERMs and well-suited for the treatment of VVA.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.steroids.2013.09.003
PMID: 24055829 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/24075094
|
1. Int J Clin Pharmacol Ther. 2013 Nov;51(11):861-7. doi: 10.5414/CP201925.
Single-dose and steady-state pharmacokinetics of ospemifene, a selective
estrogen receptor modulator, in postmenopausal women.
Koskimies P, Turunen J, Lammintausta R, Scheinin M.
OBJECTIVE: To characterize the pharmacokinetics of the oral, non-estrogen agent
ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also
called a selective estrogen receptor modulator) that was recently approved for
the treatment of dyspareunia associated with vulvar and vaginal atrophy in
postmenopausal women.
METHODS: Two open-label, Phase 1 studies were conducted to determine the
pharmacokinetics of ospemifene in healthy postmenopausal women. In the
single-dose study, 60 mg of [3H]-ospemifene was orally administered to 6
subjects. Blood, urine, and fecal samples were collected predose and serially up
to 240 hours postdose. In the multiple-dose study, 12 subjects received 60 mg of
ospemifene once daily for 9 days. Blood samples were collected predose and
serially postdose on Day 1, predose on Days 7 and 8, and predose and serially
postdose on Day 9.
RESULTS: Ospemifene exhibited high plasma protein binding and was extensively
metabolized, predominantly to 4-hydroxyospemifene and 4'-hydroxyospemifene. In
the single-dose study, ospemifene was rapidly absorbed, with a median tmax of
1.50 hours and geometric mean Cmax of 612 ng/ml. The geometric mean (CV%) t1/2
was 24.5 (21.3) hours and 29.0 (18.0) hours for ospemifene and
4-hydroxyospemifene, respectively. Fecal elimination accounted for 75% of the
administered [3H]-ospemifene dose in 240 hours. In the multiple dosing study,
steady state was reached by Day 7. The mean t1/2 at steady state for ospemifene
was 29.1 hours. High values for volume of distribution and total clearance
suggested extensive tissue distribution and efficient elimination of ospemifene.
CONCLUSIONS: In healthy postmenopausal women, ospemifene 60 mg/day reached
steady state concentrations by Day 7 and showed minimal accumulation of parent
drug or its two main metabolites, indicating that once daily dosing is
appropriate.
DOI: 10.5414/CP201925
PMID: 24075094 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23985562
|
1. Menopause. 2013 Sep;20(9):888-902; quiz 903-4. doi:
10.1097/GME.0b013e3182a122c2.
Management of symptomatic vulvovaginal atrophy: 2013 position statement of The
North American Menopause Society.
[No authors listed]
OBJECTIVE: To update and expand the previous position statement of The North
American Menopause Society (NAMS) on the management of symptomatic vulvovaginal
atrophy (VVA) in postmenopausal women.
METHODS: NAMS searched PubMed for medical literature on VVA published since
their 2007 position statement on the role of local vaginal estrogen for
treatment of vaginal atrophy in postmenopausal women. A panel of acknowledged
experts in the field of genitourinary health reviewed the literature to evaluate
new evidence on local estrogen as well as on other management options available
or in development for symptomatic VVA. The panel's conclusions and
recommendations were reviewed and approved by the NAMS Board of Trustees.
RESULTS: Symptomatic VVA can significantly impair the quality of life (QOL) of
postmenopausal women and may be underdiagnosed. In most cases, it can be managed
successfully. A number of over-the-counter and government-approved prescription
therapies available in the United States and Canada demonstrate effectiveness,
depending on the severity of VVA symptoms. These include vaginal lubricants and
moisturizers, vaginal estrogen, hormone therapy, and the selective
estrogen-receptor modulator ospemifene (indicated for dyspareunia). Long-term
studies on the endometrial safety of local estrogen and ospemifene are lacking.
Changes in the vaginal microbiome have various effects on symptoms.
CONCLUSIONS: Clinicians can improve the sexual health and QOL of postmenopausal
women by educating women about, diagnosing, and appropriately managing
symptomatic VVA. Choice of therapy depends on the severity of symptoms, the
effectiveness and safety of therapy for the individual patient, and patient
preference. Estrogen therapy is the most effective treatment for moderate to
severe symptoms, although a direct comparison of estrogen and ospemifene is not
available. Nonhormonal therapies available without a prescription provide
sufficient relief for most women with mild symptoms. When low-dose estrogen is
administered locally, a progestogen is not indicated for women without a uterus
and generally is not indicated for women with an intact uterus. However,
endometrial safety has not been studied in clinical trials beyond 1 year. There
are insufficient data to confirm the safety of local estrogen in women with
breast cancer; management of VVA should take the woman's needs and the
recommendation of her oncologist into consideration. Research on the vaginal
microbiome may lead to other therapies in the future.
DOI: 10.1097/GME.0b013e3182a122c2
PMID: 23985562 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23172542
|
1. Biofabrication. 2013 Mar;5(1):015001. doi: 10.1088/1758-5082/5/1/015001. Epub
2012 Nov 21.
Hybrid printing of mechanically and biologically improved constructs for
cartilage tissue engineering applications.
Xu T(1), Binder KW, Albanna MZ, Dice D, Zhao W, Yoo JJ, Atala A.
Author information:
(1)Wake Forest Institute for Regenerative Medicine, Wake Forest University
Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Bioprinting is an emerging technique used to fabricate viable, 3D tissue
constructs through the precise deposition of cells and hydrogels in a
layer-by-layer fashion. Despite the ability to mimic the native properties of
tissue, printed 3D constructs that are composed of naturally-derived
biomaterials still lack structural integrity and adequate mechanical properties
for use in vivo, thus limiting their development for use in load-bearing tissue
engineering applications, such as cartilage. Fabrication of viable constructs
using a novel multi-head deposition system provides the ability to combine
synthetic polymers, which have higher mechanical strength than natural
materials, with the favorable environment for cell growth provided by
traditional naturally-derived hydrogels. However, the complexity and high cost
associated with constructing the required robotic system hamper the widespread
application of this approach. Moreover, the scaffolds fabricated by these
robotic systems often lack flexibility, which further restrict their
applications. To address these limitations, advanced fabrication techniques are
necessary to generate complex constructs with controlled architectures and
adequate mechanical properties. In this study, we describe the construction of a
hybrid inkjet printing/electrospinning system that can be used to fabricate
viable tissues for cartilage tissue engineering applications. Electrospinning of
polycaprolactone fibers was alternated with inkjet printing of rabbit elastic
chondrocytes suspended in a fibrin-collagen hydrogel in order to fabricate a
five-layer tissue construct of 1 mm thickness. The chondrocytes survived within
the printed hybrid construct with more than 80% viability one week after
printing. In addition, the cells proliferated and maintained their basic
biological properties within the printed layered constructs. Furthermore, the
fabricated constructs formed cartilage-like tissues both in vitro and in vivo as
evidenced by the deposition of type II collagen and glycosaminoglycans.
Moreover, the printed hybrid scaffolds demonstrated enhanced mechanical
properties compared to printed alginate or fibrin-collagen gels alone. This
study demonstrates the feasibility of constructing a hybrid inkjet printing
system using off-the-shelf components to produce cartilage constructs with
improved biological and mechanical properties.
DOI: 10.1088/1758-5082/5/1/015001
PMID: 23172542 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23605694
|
1. Drugs. 2013 May;73(6):605-12. doi: 10.1007/s40265-013-0046-y.
Ospemifene: first global approval.
Elkinson S(1), Yang LP.
Author information:
(1)Adis R&D Insight, 41 Centorian Drive, Private Bag 65901 Mairangi Bay, North
Shore 0754, Auckland, New Zealand. dru@adis.com
Ospemifene (Osphena™) is an oral selective estrogen receptor modulator (SERM),
with tissue-specific estrogenic agonist/antagonist effects. QuatRx
Pharmaceuticals conducted the global development of the agent before licensing
it to Shionogi for regulatory filing and commercialization worldwide. Ospemifene
is the first non-estrogen treatment approved for moderate to severe dyspareunia
in women with menopause-related vulvar and vaginal atrophy. The drug is approved
in the USA, and application for EU regulatory approval is underway. This article
summarizes the milestones in the development of ospemifene leading to this first
approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar
and vaginal atrophy.
DOI: 10.1007/s40265-013-0046-y
PMID: 23605694 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24899755
|
1. Sleep. 2014 Apr 1;37(4):635-43. doi: 10.5665/sleep.3558.
Pregabalin versus pramipexole: effects on sleep disturbance in restless legs
syndrome.
Garcia-Borreguero D(1), Patrick J(2), DuBrava S(2), Becker PM(3), Lankford A(4),
Chen C(2), Miceli J(2), Knapp L(2), Allen RP(5).
Author information:
(1)Sleep Research Institute, Madrid, Spain.
(2)Pfizer Global Research and Development, Groton, CT.
(3)University of Texas Southwestern Medical Center, Dallas, TX.
(4)Sleep Disorders Center of Georgia, Atlanta, GA.
(5)Johns Hopkins University, Department of Neurology, Baltimore, MD.
STUDY OBJECTIVES: To compare pregabalin versus placebo and pramipexole for
reducing restless legs syndrome (RLS)-related sleep disturbance.
DESIGN: Randomized, double-blinded, crossover trial.
SETTING: Twenty-three US sleep centers.
PARTICIPANTS: Eighty-five individuals with moderate to severe idiopathic RLS and
associated sleep disturbance.
INTERVENTIONS: Participants were randomized across 6 treatment sequences
comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole
0.5 mg/day (n = 76), or placebo (n = 73).
MEASUREMENTS AND RESULTS: Polysomnography was conducted over 2 nights at the end
of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo)
and key secondary endpoints were analyzed for statistical significance, with
descriptive statistics for other endpoints. Pregabalin improved sleep
maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P <
0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7
vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an
increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8
vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs
placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement
arousal index (PLMAI) with pregabalin was similar to pramipexole and greater
than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in
sleep was less than for pramipexole.
CONCLUSIONS: This study demonstrated improvements in objective and subjective
measures of sleep maintenance and sleep architecture with pregabalin compared
with placebo and pramipexole. Effects of pregabalin on periodic limb movement
arousal index were comparable to pramipexole.
TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00991276;
http://clinicaltrials.gov/show/NCT00991276.
DOI: 10.5665/sleep.3558
PMCID: PMC4044751
PMID: 24899755 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25641220
|
1. Adv Mater. 2015 Mar 4;27(9):1607-14. doi: 10.1002/adma.201405076. Epub 2015
Jan 16.
A multimaterial bioink method for 3D printing tunable, cell-compatible
hydrogels.
Rutz AL(1), Hyland KE, Jakus AE, Burghardt WR, Shah RN.
Author information:
(1)Simpson Querrey Institute for BioNanotechnology, Chicago, IL, 60611, USA;
Department of Biomedical Engineering, Evanston, IL, 60208, USA.
A multimaterial bio-ink method using polyethylene glycol crosslinking is
presented for expanding the biomaterial palette required for 3D bioprinting of
more mimetic and customizable tissue and organ constructs. Lightly crosslinked,
soft hydrogels are produced from precursor solutions of various materials and 3D
printed. Rheological and biological characterizations are presented, and the
promise of this new bio-ink synthesis strategy is discussed.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/adma.201405076
PMCID: PMC4476973
PMID: 25641220 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25839977
|
1. Otol Neurotol. 2015 Jun;36(5):793-5. doi: 10.1097/MAO.0000000000000750.
3D Printed Pediatric Temporal Bone: A Novel Training Model.
Longfield EA(1), Brickman TM, Jeyakumar A.
Author information:
(1)Department of Otorhinolaryngology, Louisiana State University-Health Science
Center, New Orleans, Louisiana, U.S.A.
OBJECTIVE: Temporal bone dissection is a fundamental element of otologic
training. Cadaveric temporal bones (CTB) are the gold standard surgical training
model; however, many institutions do not have ready access to them and their
cost can be significant: $300 to $500. Furthermore, pediatric cadaveric temporal
bones are not readily available. Our objective is to develop a pediatric
temporal bone model.
STUDY DESIGN: Temporal bone model.
SETTING: Tertiary Children's Hospital.
SUBJECTS: Pediatric patient model.
METHODS: We describe the novel use of a 3D printer for the generation of a
plaster training model from a pediatric high- resolution CT temporal bone scan
of a normal pediatric temporal bone.
RESULTS: Three models were produced and were evaluated. The models utilized
multiple colors (white for bone, yellow for the facial nerve) and were of high
quality. Two models were drilled as a proof of concept and found to be an
acceptable facsimile of the patient's anatomy, rendering all necessary surgical
landmarks accurately. The only negative comments pertaining to the 3D printed
temporal bone as a training model were the lack of variation in hardness between
cortical and cancellous bone, noting a tactile variation from cadaveric temporal
bones.
CONCLUSION: Our novel pediatric 3D temporal bone training model is a viable,
low-cost training option for previously inaccessible pediatric temporal bone
training. Our hope is that, as 3D printers become commonplace, these models
could be rapidly reproduced, allowing for trainees to print models of patients
before performing surgery on the living patient.
DOI: 10.1097/MAO.0000000000000750
PMID: 25839977 [Indexed for MEDLINE]
|
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