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http://www.ncbi.nlm.nih.gov/pubmed/9389494 | 1. Endocrinology. 1997 Dec;138(12):5144-52. doi: 10.1210/endo.138.12.5599.
Expression of chicken hepatic type I and type III iodothyronine deiodinases
during embryonic development.
Van der Geyten S(1), Sanders JP, Kaptein E, Darras VM, Kühn ER, Leonard JL,
Visser TJ.
Author information:
(1)Department of Internal Medicine III, Erasmus University Medical School,
Rotterdam, The Netherlands.
In embryonic chicken liver (ECL) two types of iodothyronine deiodinases are
expressed: D1 and D3. D1 catalyzes the activation as well as the inactivation of
thyroid hormone by outer and inner ring deiodination, respectively. D3 only
catalyzes inner ring deiodination. D1 and D3 have been cloned from mammals and
amphibians and shown to contain a selenocysteine (Sec) residue. We characterized
chicken D1 and D3 complementary DNAs (cDNAs) and studied the expression of
hepatic D1 and D3 messenger RNAs (mRNAs) during embryonic development.
Oligonucleotides based on two amino acid sequences strongly conserved in the
different deiodinases (NFGSCTSecP and YIEEAH) were used for reverse
transcription-PCR of poly(A+) RNA isolated from embryonic day 17 (E17) chicken
liver, resulting in the amplification of two 117-bp DNA fragments. Screening of
an E17 chicken liver cDNA library with these probes led to the isolation of two
cDNA clones, ECL1711 and ECL1715. The ECL1711 clone was 1360 bp long and lacked
a translation start site. Sequence alignment showed that it shared highest
sequence identity with D1s from other vertebrates and that the coding sequence
probably lacked the first five nucleotides. An ATG start codon was engineered by
site-directed mutagenesis, generating a mutant (ECL1711M) with four additional
codons (coding for MGTR). The open reading frame of ECL1711M coded for a
249-amino acid protein showing 58-62% identity with mammalian D1s. An in-frame
TGA codon was located at position 127, which is translated as Sec in the
presence ofa Sec insertion sequence (SECIS) identified in the 3'-untranslated
region. Enzyme activity expressed in COS-1 cells by transfection with ECL1711M
showed the same catalytic, substrate, and inhibitor specificities as native
chicken D1. The ECL1715 clone was 1366 bp long and also lacked a translation
start site. Sequence alignment showed that it was most homologous with D3 from
other species and that the coding sequence lacked approximately the first 46
nucleotides. The deduced amino acid sequence showed 62-72% identity with the D3
sequences from other species, including a putative Sec residue at a
corresponding position. The 3'-untranslated region of ECL1715 also contained a
SECIS element. These results indicate that ECL1711 and ECL1715 are
near-full-length cDNA clones for chicken D1 and D3 selenoproteins, respectively.
The ontogeny of D1 and D3 expression in chicken liver was studied between E14
and 1 day after hatching (C1). D1 activity showed a gradual increase from E14
until C1, whereas D1 mRNA level remained relatively constant. D3 activity and
mRNA level were highly significantly correlated, showing an increase from E14 to
E17 and a strong decrease thereafter. These results suggest that the regulation
of chicken hepatic D3 expression during embryonic development occurs
predominantly at the pretranslational level.
DOI: 10.1210/endo.138.12.5599
PMID: 9389494 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18721481 | 1. Virol J. 2008 Aug 23;5:99. doi: 10.1186/1743-422X-5-99.
A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr:
potential impact on CTL epitopes.
Srinivasan A(1), Ayyavoo V, Mahalingam S, Kannan A, Boyd A, Datta D,
Kalyanaraman VS, Cristillo A, Collman RG, Morellet N, Sawaya BE, Murali R.
Author information:
(1)Department of Microbiology and Immunology, Thomas Jefferson University,
Philadelphia, PA 19107, USA. [email protected]
The enormous genetic variability reported in HIV-1 has posed problems in the
treatment of infected individuals. This is evident in the form of HIV-1
resistant to antiviral agents, neutralizing antibodies and cytotoxic T
lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has
been suggested that a comprehensive analysis of the polymorphisms in HIV
proteins is of value for understanding the virus transmission and pathogenesis
as well as for the efforts towards developing anti-viral therapeutics and
vaccines. This study, for the first time, describes an in-depth analysis of
genetic variation in Vpr using information from global HIV-1 isolates involving
a total of 976 Vpr sequences. The polymorphisms at the individual amino acid
level were analyzed. The residues 9, 33, 39, and 47 showed a single variant
amino acid compared to other residues. There are several amino acids which are
highly polymorphic. The residues that show ten or more variant amino acids are
15, 16, 28, 36, 37, 48, 55, 58, 59, 77, 84, 86, 89, and 93. Further, the variant
amino acids noted at residues 60, 61, 34, 71 and 72 are identical.
Interestingly, the frequency of the variant amino acids was found to be low for
most residues. Vpr is known to contain multiple CTL epitopes like protease,
reverse transcriptase, Env, and Gag proteins of HIV-1. Based on this, we have
also extended our analysis of the amino acid polymorphisms to the experimentally
defined and predicted CTL epitopes. The results suggest that amino acid
polymorphisms may contribute to the immune escape of the virus. The available
data on naturally occurring polymorphisms will be useful to assess their
potential effect on the structural and functional constraints of Vpr and also on
the fitness of HIV-1 for replication.
DOI: 10.1186/1743-422X-5-99
PMCID: PMC2553080
PMID: 18721481 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22994218 | 1. Ann N Y Acad Sci. 2012 Sep;1268:26-34. doi: 10.1111/j.1749-6632.2012.06668.x.
The ischemic penumbra: how does tissue injury evolve?
Heiss WD(1).
Author information:
(1)Max Planck Institute for Neurological Research, Cologne, Germany.
[email protected]
An ischemic penumbra has the potential for functional recovery provided that
local blood flow can be reestablished, but irreversible damage will develop
without sufficient reperfusion, depending on the interaction of severity and
duration of ischemia. With acute flows below the threshold required for
maintenance of basic housekeeping, injury in the core is established within a
few minutes. During the subacute phase, the irreversible damage expands into the
penumbra: multiple electrical and biological signals are triggered by
periinfarct, spreading depression-like depolarizations leading to hypoxia and
stepwise increase in lactate. Usually within 6 to 8 hours, all the penumbra are
converted into irreversible infarcts. In a delayed phase, secondary phenomena
may cause additional tissue damage: disruption of the tight junctions results in
vasogenic edema, leading to increase of water content and damage expansion.
Neutrophils and cytokinins cause secondary inflammation, inducing further damage
in periinfarct regions and connecting fiber tracts. Multimodal imaging might be
able to differentiate among the tissue compartments affected by acute, subacute,
or delayed ischemic damage, and thereby might provide the basis for
phase-specific treatment strategies.
© 2012 New York Academy of Sciences.
DOI: 10.1111/j.1749-6632.2012.06668.x
PMID: 22994218 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2189307 | 1. Am J Med. 1990 Jun;88(6):631-7. doi: 10.1016/0002-9343(90)90531-h.
Thyroid hormone and the cardiovascular system.
Klein I(1).
Author information:
(1)Department of Medicine, North Shore University Hospital, Cornell University
Medical College, Manhasset, New York 11030.
To understand the pathophysiology of thyroid heart disease, it is necessary to
recognize that thyroid hormone has effects on both the peripheral circulation
and the myocardium. One of the earliest responses to thyroid hormone
administration is a decline in systemic vascular resistance and an increase in
cardiac output and cardiac contractility. In many ways, this response is similar
to the cardiovascular response to exercise and is associated with increased left
ventricular work. The majority of cardiac adaptations to changes in thyroid
function are physiologic; however, certain patients do demonstrate clinical
evidence of cardiac disease. Atrial arrhythmias, limitations in exercise
tolerance, and congestive heart failure are reported to occur as a result of
hyperthyroidism and are more common in older patients. Thyroid hormone also
plays an important role in the regulation of blood pressure. Diastolic
hypertension is a common accompaniment of hypothyroidism. By understanding the
mechanisms by which thyroid hormone affects both the peripheral circulation as
well as the myocardium, it is possible to predict the clinical response to the
treatment of various thyroid disease states.
DOI: 10.1016/0002-9343(90)90531-h
PMID: 2189307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15530662 | 1. Brain Res Mol Brain Res. 2004 Nov 24;131(1-2):131-5. doi:
10.1016/j.molbrainres.2004.08.006.
Upregulation of amyloid precursor protein isoforms containing Kunitz protease
inhibitor in dementia with Lewy bodies.
Beyer K(1), Lao JI, Carrato C, Mate JL, López D, Ferrer I, Ariza A.
Author information:
(1)Department of Pathology, Hospital Universitari Germans Trias i Pujol,
Autonomous University of Barcelona, Spain. [email protected]
Amyloid precursor protein (APP) is involved in the accumulation of
alpha-synuclein, the main component of Lewy bodies. It is currently unknown,
however, whether any of the APP isoforms is instrumental in alpha-synuclein
deposition in dementia with Lewy bodies (DLB). Using real-time RT-PCR, we have
studied relative mRNA expression levels of APP isoforms in frozen postmortem
frontal cortices of DLB patients, Alzheimer disease (AD) patients, and control
subjects. Of the three main APP isoforms, the two with a Kunitz protease
inhibitory (KPI) motif (APP770 and APP751) were found to be specifically
overexpressed in the frontal cortices of DLB patients when compared with
controls and AD patients. These findings suggest a specific role of APP isoforms
containing Kunitz protease inhibitor in DLB pathogenesis.
DOI: 10.1016/j.molbrainres.2004.08.006
PMID: 15530662 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18779539 | 1. Oncologist. 2008 Sep;13(9):978-92. doi: 10.1634/theoncologist.2008-0056. Epub
2008 Sep 8.
Therapeutic application of noncytotoxic molecular targeted therapy in gliomas:
growth factor receptors and angiogenesis inhibitors.
Idbaih A(1), Ducray F, Sierra Del Rio M, Hoang-Xuan K, Delattre JY.
Author information:
(1)INSERM, Unité 711, Paris, France. [email protected]
Growth factor receptors and angiogenesis play major roles in the oncogenesis of
gliomas. Over the last several years, several noncytotoxic molecular targeted
therapies have been developed against growth factor receptors and tumor
angiogenesis. In gliomas, two main anti-growth factor receptor strategies have
been evaluated in phase I/II clinical trials: (a) small molecule tyrosine kinase
inhibitors (TKIs) and (b) monoclonal antibodies that target growth factors or
growth factor receptors other than vascular endothelial growth factor (VEGF). Up
to now, few glioma patients have responded to small TKIs (0%-14%) or monoclonal
antibodies (three case reports) delivered as a single agent. Greater doses,
combined therapies, as well as the identification of molecular biomarkers
predictive of response and resistance are important in order to optimize drug
delivery and improve efficacy. Antiangiogenic therapies are promising for the
treatment of gliomas. Thalidomide and metronomic chemotherapy were the first
antiangiogenic strategies evaluated, but they have shown only modest activity.
Recent studies of bevacizumab, an anti-VEGF antibody, and irinotecan, a
topoisomerase I inhibitor, have demonstrated a high response rate, suggesting
that targeted antiangiogenic therapies may play a significant role in the
management of high-grade gliomas in the future. However, the toxicity profiles
of these agents are not fully defined and the radiological evaluation of
possible tumor response is challenging. Clinical evaluation of several VEGF
receptor TKIs is currently ongoing; one of these inhibitors, cediranib, has
already demonstrated interesting activity as a single agent. The integrin
inhibitor cilengitide represents another promising strategy.
DOI: 10.1634/theoncologist.2008-0056
PMID: 18779539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21914860 | 1. FASEB J. 2012 Jan;26(1):40-50. doi: 10.1096/fj.11-186841. Epub 2011 Sep 13.
Mitochondrial T3 receptor p43 regulates insulin secretion and glucose
homeostasis.
Blanchet E(1), Bertrand C, Annicotte JS, Schlernitzauer A, Pessemesse L, Levin
J, Fouret G, Feillet-Coudray C, Bonafos B, Fajas L, Cabello G, Wrutniak-Cabello
C, Casas F.
Author information:
(1)UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1,
Montpellier, France.
Thyroid hormone is a major determinant of energy expenditure and a key regulator
of mitochondrial activity. We have previously identified a mitochondrial
triiodothyronine receptor (p43) that acts as a mitochondrial transcription
factor of the organelle genome, which leads, in vitro and in vivo, to a
stimulation of mitochondrial biogenesis. Here we generated mice specifically
lacking p43 to address its physiological influence. We found that p43 is
required for normal glucose homeostasis. The p43(-/-) mice had a major defect in
insulin secretion both in vivo and in isolated pancreatic islets and a loss of
glucose-stimulated insulin secretion. Moreover, a high-fat/high-sucrose diet
elicited more severe glucose intolerance than that recorded in normal animals.
In addition, we observed in p43(-/-) mice both a decrease in pancreatic islet
density and in the activity of complexes of the respiratory chain in isolated
pancreatic islets. These dysfunctions were associated with a down-regulation of
the expression of the glucose transporter Glut2 and of Kir6.2, a key component
of the K(ATP) channel. Our findings establish that p43 is an important regulator
of glucose homeostasis and pancreatic β-cell function and provide evidence for
the first time of a physiological role for a mitochondrial endocrine receptor.
DOI: 10.1096/fj.11-186841
PMID: 21914860 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16962805 | 1. Mol Cell. 2006 Sep 15;23(6):787-99. doi: 10.1016/j.molcel.2006.08.018. Epub
2006 Sep 7.
Establishment of sister chromatid cohesion at the S. cerevisiae replication
fork.
Lengronne A(1), McIntyre J, Katou Y, Kanoh Y, Hopfner KP, Shirahige K, Uhlmann
F.
Author information:
(1)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London
WC2A 3PX, United Kingdom.
Two identical sister copies of eukaryotic chromosomes are synthesized during S
phase. To facilitate their recognition as pairs for segregation in mitosis,
sister chromatids are held together from their synthesis onward by the
chromosomal cohesin complex. Replication fork progression is thought to be
coupled to establishment of sister chromatid cohesion, facilitating
identification of replication products, but evidence for this has remained
circumstantial. Here we show that three proteins required for sister chromatid
cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along
chromosomes with, replication forks. The ring-shaped cohesin complex is loaded
onto chromosomes before S phase in an ATP hydrolysis-dependent reaction.
Cohesion establishment during DNA replication follows without further cohesin
recruitment and without need for cohesin to re-engage an ATP hydrolysis motif
that is critical for its initial DNA binding. This provides evidence for
cohesion establishment in the context of replication forks and imposes
constraints on the mechanism involved.
DOI: 10.1016/j.molcel.2006.08.018
PMID: 16962805 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1473624 | 1. Differentiation. 1992 Oct;51(2):105-12. doi:
10.1111/j.1432-0436.1992.tb00686.x.
Early heart development in the chick embryo: effects of isotretinoin on cell
proliferation, alpha-actin synthesis, and development of contractions.
Wiens DJ(1), Mann TK, Fedderson DE, Rathmell WK, Franck BH.
Author information:
(1)Department of Biology, University of Northern Iowa, Cedar Falls 50614.
Isotretinoin is a potent retinoic acid used in the treatment of skin disorders.
Though very effective, it is teratogenic if administered during pregnancy, and
its teratogenic effect may be related to the normal activity of retinoids as
signalling molecules in the embryo. Although its exact mechanism of action is
unknown, it has been suggested that it causes its characteristic pattern of
defects that includes heart defects, by inhibiting the migration of neural crest
cells. However, other effects on cells are known. We studied early cardiac cell
proliferation using incorporation of bromodeoxyuridine (BrdU) and detection with
a monoclonal anti-BrdU. Proliferation in heart tissue of whole embryo cultures
was inhibited in medium with 10(-6) M isotretinoin to 62% of the control level
in myocardium. We studied its effects in culture on precardiac explant
development in the absence of the neural crests. Culture of precardiac
mesodermal-endodermal explants revealed that development of heart vesicles from
the mesoderm was little affected, but the development of heartbeat was inhibited
depending on dose in the 10(-5) to 10(-7) M range. The effect on development of
contractions was augmented in the presence of serum; it could be duplicated by
all-trans-retinoic acid, and it was reversible. Synthesis of the alpha-actin
isotype, analyzed by isoelectric focusing, was found to be inhibited or delayed.
The results suggest multiple effects of retinoids on growth, morphogenesis, and
differentiation of early cardiac tissue, and are discussed in relation to the
potential role of retinoids in early embryogenesis.
DOI: 10.1111/j.1432-0436.1992.tb00686.x
PMID: 1473624 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23314924 | 1. Int J Clin Oncol. 2014 Feb;19(1):68-73. doi: 10.1007/s10147-012-0512-7. Epub
2013 Jan 12.
A multicenter prospective study to evaluate bone fracture related to adjuvant
anastrozole in Japanese postmenopausal women with breast cancer: two-year
interim analysis of Saitama Breast Cancer Clinical Study Group (SBCCSG-06).
Takeuchi H(1), Takei H, Futsuhara K, Yoshida T, Kojima M, Kai T, Tabei T.
Author information:
(1)Department of Breast Oncology, Saitama Medical University International
Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
BACKGROUND: Because of its superior efficacy to tamoxifen, anastrozole has been
widely used in Japan as an adjuvant treatment for postmenopausal,
hormone-responsive breast cancer patients. However, anastrozole may affect bone
in Japanese patients similar to its effects in Western patients. The aim of this
study is to evaluate the rate of bone fracture and bone mineral density (BMD)
during anastrozole treatment in Japanese patients.
PATIENTS AND METHODS: In this study, 350 postmenopausal women with
hormone-responsive, stage I to IIIA breast cancer were enrolled and scheduled to
receive adjuvant anastrozole treatment for up to 5 years. Patients underwent
clinical examination for bone fractures and annual measurement of BMD during
treatment.
RESULTS: After a median follow-up of 33.0 months, bone fractures occurred in 1.8
%. Annual fracture rates were 0.3 and 1.2 % during the first and second year,
respectively. The overall median BMD significantly decreased, measuring 87.5,
84.3, and 83.5 % at baseline and after 1 and 2 years, respectively.
Musculoskeletal disorders were the most common (26.1 %), and hot flashes were
the second most common adverse event (7.9 %). Severe adverse events occurred in
5.5 % of all the cases.
CONCLUSIONS: In this interim analysis, the bone fracture rate was lower than
that in the Western population despite a significant reduction of BMD after 2
years of treatment with anastrozole. Adjuvant anastrozole treatment was well
tolerated in Japanese postmenopausal women with breast cancer. Long-term
follow-up data is necessary to elucidate the racial disparities of the safety
profile of anastrozole.
DOI: 10.1007/s10147-012-0512-7
PMID: 23314924 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10941840 | 1. Immunogenetics. 2000 Jul;51(8-9):688-94. doi: 10.1007/s002510000193.
Quantitative analysis of XG blood group and CD99 antigens on human red cells.
Fouchet C(1), Gane P, Cartron JP, Lopez C.
Author information:
(1)Institut National de la Transfusion Sanguine, INSERM U76, Paris, France.
CD99, the product of the MIC2 gene, exhibits an erythroid-specific quantitative
polymorphism co-regulated with the Xga blood group polymorphism. The
co-expression of X-linked MIC2 and XG genes is presumably controlled at the
transcriptional level by a single XGR locus in the pseudoautosomal region of
sexual chromosomes. This locus is composed of two alleles, XGR(low) and
XGR(high), which determine low or high CD99 levels (CD99-L, CD99-H) and the
Xg(a-)/ Xg(a+) status. To test this hypothesis, the phenotypic relationship
between Xga and CD99 antigens on human RBCs was investigated by quantitative
flow cytometry using NBL-1 (anti-Xga) and 12E7 (anti-CD99) monoclonal antibodies
and semi-quantitative estimate of membrane proteins and RNA by Western blot and
Northern blot, respectively. The antibody binding capacity of RBCs, which is an
estimation of the antigen density, was determined for 118 blood donors including
60 males and 58 females. Xg(a+) RBCs, which all belong to the group of CD99-H
expressors, carry 159+/-13 and 960+/-50 copies of Xga and CD99 molecules/cell,
respectively. Xg(a-) RBCs have no Xga antigen, but are subdivided into CD99-H
(all male) and CD99-L expressors carrying 747+/-28 and 200+/-22 CD99
copies/cell, respectively, with identical CD99 levels between CD99-L males and
females. However, among males, the CD99 expression was higher in Xg(a+) than in
Xg(a-)/CD99-H individuals (P<0.01). In addition, CD99-H expressors in Xg(a+)
males could be clearly subdivided into two categories, high and super high
expressors, which are presumably heterozygous and homozygous for the XGR(high)
allele, which fits the above hypothesis. This was not the case for Xg(a+)
females where CD99-H subcategories were not found. Quantitative differences were
confirmed by Western blot analysis of red cell membrane preparations from
individuals of different Xga and CD99 phenotypes and by Northern blot analysis
showing that the reticulocytes from CD99-L individuals expressed a reduced level
of MIC2 transcripts compared to CD99-H donors. These findings further support
the hypothesis of a single genetic control of CD99 and Xga expression by the XGR
locus.
DOI: 10.1007/s002510000193
PMID: 10941840 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22101275 | 1. Cell Cycle. 2011 Dec 1;10(23):4110-8. doi: 10.4161/cc.10.23.18243. Epub 2011
Dec 1.
Drosophila endocytic neoplastic tumor suppressor genes regulate Sav/Wts/Hpo
signaling and the c-Jun N-terminal kinase pathway.
Robinson BS(1), Moberg KH.
Author information:
(1)Department of Cell Biology, Emory University School of Medicine, Atlanta, GA,
USA.
Genetic screens in the fruit fly Drosophila melanogaster have identified a class
of neoplastic tumor suppressor genes (endocytic nTSGs), which encode proteins
that localize to endosomes and facilitate the trafficking of membrane-bound
receptors and adhesion molecules into the degradative lysosome. Loss of
endocytic nTSGs transforms imaginal disc epithelia into highly proliferative,
invasive tissues that fail to differentiate and display defects in cellular
apicobasal polarity, adhesion and tissue architecture. As vertebrate homologs of
some Drosophila nTSGs are linked to tumor formation, identifying molecular
changes in signaling associated with nTSG loss could inform understanding of
neoplastic transformation in vertebrates. Here we show that mutations in genes
that act at multiple steps of the endolysosomal pathway lead to autonomous
activation of the Sav/Wts/Hpo (SWH) transcriptional effector Yki (YAP/TAZ in
vertebrates) and the Jun N-terminal kinase (JNK), which is known to promote Yki
activity in cells with disrupted polarity. Yki and JNK activity are elevated by
mutations at multiple steps in the endolysosomal pathway including mutations in
the AP-2σ gene, which encodes a component of the AP-2 adaptor complex that
recruits cargoes into clathrin-coated pits for subsequent internalization.
Moreover, reduction of JNK activity can decrease elevated Yki-signaling caused
by altered endocytosis. These studies reveal a broad requirement for components
of the endocytic pathway in regulating SWH and JNK outputs, and place Drosophila
endocytic nTSGs into a network that involving two major signaling pathways
implicated in oncogenesis.
DOI: 10.4161/cc.10.23.18243
PMCID: PMC3272291
PMID: 22101275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15342557 | 1. Genome Res. 2004 Sep;14(9):1719-25. doi: 10.1101/gr.2855504.
Widespread RNA editing of embedded alu elements in the human transcriptome.
Kim DD(1), Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, Gabriel A.
Author information:
(1)Department of Molecular Biology and Biochemistry, Rutgers University,
Piscataway, New Jersey 08854, USA.
More than one million copies of the approximately 300-bp Alu element are
interspersed throughout the human genome, with up to 75% of all known genes
having Alu insertions within their introns and/or UTRs. Transcribed Alu
sequences can alter splicing patterns by generating new exons, but other impacts
of intragenic Alu elements on their host RNA are largely unexplored. Recently,
repeat elements present in the introns or 3'-UTRs of 15 human brain RNAs have
been shown to be targets for multiple adenosine to inosine (A-to-I) editing.
Using a statistical approach, we find that editing of transcripts with embedded
Alu sequences is a global phenomenon in the human transcriptome, observed in
2674 ( approximately 2%) of all publicly available full-length human cDNAs (n =
128,406), from >250 libraries and >30 tissue sources. In the vast majority of
edited RNAs, A-to-I substitutions are clustered within transcribed sense or
antisense Alu sequences. Edited bases are primarily associated with retained
introns, extended UTRs, or with transcripts that have no corresponding known
gene. Therefore, Alu-associated RNA editing may be a mechanism for marking
nonstandard transcripts, not destined for translation.
DOI: 10.1101/gr.2855504
PMCID: PMC515317
PMID: 15342557 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22092535 | 1. Clin Exp Allergy. 2012 May;42(5):712-37. doi:
10.1111/j.1365-2222.2011.03854.x. Epub 2011 Sep 23.
Molecular and clinical rationale for therapeutic targeting of interleukin-5 and
its receptor.
Molfino NA(1), Gossage D, Kolbeck R, Parker JM, Geba GP.
Author information:
(1)MedImmune, LLC, Gaithersburg, MD 20878, USA. [email protected]
Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation,
maturation, migration, development, survival, trafficking and effector function
of blood and local tissue eosinophils, in addition to basophils and mast cells.
The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts
in conformationally dynamic ways with the receptor's βc subunit, an aggregate of
domains it shares with binding sites of IL-3 and granulocyte-macrophage
colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune
responses characterizing numerous diseases, such as asthma, atopic dermatitis,
chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases,
hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal
polyposis. Although corticosteroid therapy is the primary treatment for these
diseases, a substantial number of patients exhibit incomplete responses and
suffer side-effects. Two monoclonal antibodies have been designed to neutralize
IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability
to reduce blood and tissue eosinophil counts. One additional monoclonal
antibody, benralizumab (MEDI-563), has been developed to target IL-5R and
attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All
three monoclonal antibodies are being clinically evaluated. Antisense
oligonucleotide technology targeting the common βc IL-5R subunit is also being
used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small
interfering RNA technology has also been used therapeutically to inhibit the
expression of IL-5 in animal models. This review summarizes the structural
interactions between IL-5 and IL-5R and the functional consequences of such
interactions, and describes the pre-clinical and clinical evidence supporting
IL-5R as a therapeutic target.
© 2011 MedImmune, LLC.
DOI: 10.1111/j.1365-2222.2011.03854.x
PMID: 22092535 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16969096 | 1. Cell Cycle. 2006 Sep;5(18):2082-6. doi: 10.4161/cc.5.18.3209. Epub 2006 Sep
15.
Synphilin isoforms and the search for a cellular model of lewy body formation in
Parkinson's disease.
Eyal A(1), Engelender S.
Author information:
(1)Department of Pharmacology, The B. Rappaport Institute of Medical Research,
Technion-Israel Institute of Technology, Haifa, Israel.
A common finding in many neurodegenerative diseases is the presence of inclusion
bodies made of aggregated proteins in neurons of affected brain regions. In
Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and
their main component is alpha-synuclein. Although many studies have suggested
that inclusion bodies may be cell protective, it is still not clear whether Lewy
bodies promote or inhibit dopaminergic cell death in Parkinson's disease.
Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies.
Accumulation of ubiquitylated synphilin-1 leads to massive formation of
inclusion bodies, which resemble Lewy bodies by their ability to recruit
alpha-synuclein. We have recently isolated an isoform of synphilin-1,
synphilin-1A, that spontaneously aggregates in cells, and is present in
detergent-insoluble fractions of brain protein samples from
alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity
and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with
concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein
interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies
in neurons together with synphilin-1, further indicates that synphilin-1A cell
model is relevant for research on Parkinson's disease. Synphilin-1A cell model
may help provide important insights regarding the role of inclusion bodies in
Parkinson's disease and other neurodegenerative disorders.
DOI: 10.4161/cc.5.18.3209
PMID: 16969096 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22495932 | 1. Nucleic Acids Res. 2012 Aug;40(14):6800-7. doi: 10.1093/nar/gks321. Epub 2012
Apr 11.
The SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters at the imprinted
Prader-Willi locus generate canonical box C/D snoRNAs.
Bortolin-Cavaillé ML(1), Cavaillé J.
Author information:
(1)Laboratoire de Biologie Moléculaire Eucaryote, UPS, Université de Toulouse,
Toulouse, France.
The imprinted Snurf-Snrpn chromosomal domain contains two large arrays of
tandemly repeated, paternally expressed box C/D small-nucleolar RNA (snoRNA)
genes: the SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters believed
to play key roles in the fine-tuning of serotonin receptor (5-HT2C) pre-mRNA
processing and in the etiology of the Prader-Willi Syndrome (PWS), respectively.
SNORD115 and SNORD116 were recently proposed to undergo significant conversion
into shorter RNA species, the so-called psnoRNAs. Here, we provide evidence that
argues against the existence of abundant psnoRNAs in human or mouse brain.
Instead, we characterize a previously unsuspected low-abundance,
fibrillarin-associated SNORD115-derived smaller RNA species. Based on these
findings, we strongly recommend that PWS-encoded SNORD115 and SNORD116 be
considered as bona fide box C/D snoRNAs.
DOI: 10.1093/nar/gks321
PMCID: PMC3413130
PMID: 22495932 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25371407 | 1. EMBO J. 2015 Jan 2;34(1):81-96. doi: 10.15252/embj.201488958. Epub 2014 Nov 4.
Identification of Cdk targets that control cytokinesis.
Kuilman T(1), Maiolica A(2), Godfrey M(3), Scheidel N(3), Aebersold R(4),
Uhlmann F(1).
Author information:
(1)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute Lincoln's Inn Fields Laboratories, London, UK [email protected]
[email protected].
(2)Department of Biology, Institute of Molecular Systems Biology, Eidgenössische
Technische Hochschule (ETH) Zürich, Zurich, Switzerland.
(3)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute Lincoln's Inn Fields Laboratories, London, UK.
(4)Department of Biology, Institute of Molecular Systems Biology, Eidgenössische
Technische Hochschule (ETH) Zürich, Zurich, Switzerland Faculty of Science,
University of Zurich, Zurich, Switzerland.
The final event of the eukaryotic cell cycle is cytokinesis, when two new
daughter cells are born. How the timing and execution of cytokinesis is
controlled is poorly understood. Here, we show that downregulation of
cyclin-dependent kinase (Cdk) activity, together with upregulation of its
counteracting phosphatase Cdc14, controls each of the sequential steps of
cytokinesis, including furrow ingression, membrane resolution and cell
separation in budding yeast. We use phosphoproteome analysis of mitotic exit to
identify Cdk targets that are dephosphorylated at the time of cytokinesis. We
then apply a new and widely applicable tool to generate conditionally
phosphorylated proteins to identify those whose dephosphorylation is required
for cytokinesis. This approach identifies Aip1, Ede1 and Inn1 as cytokinetic
regulators. Our results suggest that cytokinesis is coordinately controlled by
the master cell cycle regulator Cdk together with its counteracting phosphatase
and that it is executed by concerted dephosphorylation of Cdk targets involved
in several cell biological processes.
© 2014 The Authors. Published under the terms of the CC BY 4.0 license.
DOI: 10.15252/embj.201488958
PMCID: PMC4291482
PMID: 25371407 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24805245 | 1. Nature. 2014 Jun 12;510(7504):293-297. doi: 10.1038/nature13234. Epub 2014 May
4.
A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic
replisome.
Simon AC(#)(1), Zhou JC(#)(2), Perera RL(1), van Deursen F(3), Evrin C(4),
Ivanova ME(1), Kilkenny ML(1), Renault L(2), Kjaer S(5), Matak-Vinković D(6),
Labib K(4), Costa A(2), Pellegrini L(1).
Author information:
(1)Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
(2)Clare Hall Laboratories, Cancer Research U.K. London Research Institute,
London EN6 3LD, UK.
(3)Cancer Research U.K. Manchester Institute, University of Manchester,
Manchester M20 4BX, UK.
(4)MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee,
Dundee DD1 5EH, UK.
(5)Protein purification, Cancer Research U.K. London Research Institute, London
WC2A 3LY, UK.
(6)Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
(#)Contributed equally
Efficient duplication of the genome requires the concerted action of helicase
and DNA polymerases at replication forks to avoid stalling of the replication
machinery and consequent genomic instability. In eukaryotes, the physical
coupling between helicase and DNA polymerases remains poorly understood. Here we
define the molecular mechanism by which the yeast Ctf4 protein links the
Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase α (Pol α) within the
replisome. We use X-ray crystallography and electron microscopy to show that
Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends
on a β-propeller domain in the carboxy-terminal half of the protein, which is
fused to a helical extension that protrudes from one face of the trimeric disk.
Critically, Pol α and the CMG helicase share a common mechanism of interaction
with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol
α and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks
onto the exposed helical extension of a Ctf4 protomer within the trimer.
Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to
three partner proteins, including the simultaneous association with both Pol α
and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol α to
one CMG helicase within the replisome, providing a new model for lagging-strand
synthesis in eukaryotes that resembles the emerging model for the simpler
replisome of Escherichia coli. The ability of Ctf4 to act as a platform for
multivalent interactions illustrates a mechanism for the concurrent recruitment
of factors that act together at the fork.
DOI: 10.1038/nature13234
PMCID: PMC4059944
PMID: 24805245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22281412 | 1. Can J Cardiol. 2012 Mar-Apr;28(2):215-21. doi: 10.1016/j.cjca.2011.11.007.
Epub 2012 Jan 26.
Inhibition of sPLA2 and endothelial function: a substudy of the SPIDER-PCI
trial.
Lavi S(1), Thorpe K, Luca MC, Liuni A, Floras J, Horlick EM, Ing D, Osten MD,
Overgaard CB, Lan J, Parker JD, Cantor WJ, Džavík V.
Author information:
(1)London Health Sciences Centre, Toronto, Ontario, Canada; University of
Western Ontario, London, Ontario, Canada. [email protected]
BACKGROUND: Inflammation plays an important role in the pathophysiology of
atherosclerosis and endothelial dysfunction, and occurs after percutaneous
coronary intervention (PCI). We evaluated whether endothelial function is
attenuated after PCI and if inhibition of secretory phospholipase A2 (sPLA2)
activity augments endothelial function and coronary flow reserve (CFR) in these
patients.
METHODS: In the sPLA2 Inhibition to Decrease Enzyme Release After Percutaneous
Coronary Intervention (SPIDER-PCI) study, patients undergoing elective PCI were
randomized to receive Varespladib (Anthera Pharmaceuticals Inc, San Mateo, CA),
an inhibitor of sPLA2, or placebo 3-5 days prior to PCI and for 5 days after
PCI. In this substudy, endothelial function was assessed in 31 patients by
flow-mediated dilation (FMD) before treatment and on the day after PCI, while
taking study medication. During the PCI procedure, CFR was assessed using a
Doppler guide wire.
RESULTS: Baseline and procedural characteristics were comparable in both groups
and sPLA2 activity was similar at baseline. After PCI, sPLA2 activity decreased
only in the Varespladib group (2.9 ± 0.9 to 0.5 ± 0.4 ng/mL), and
high-sensitivity C-reactive protein (hsCRP) increased by more than 100% in both
groups. FMD at baseline was 3.66 ± 2.45% (Varespladib) and 3.37 ± 1.73%
(placebo) with nonsignificant increase in both groups after PCI. The effect of
Varespladib on FMD, adjusted for pre-PCI FMD by linear regression, was -1.16 ±
1.68%; P = 0.5. CFR was 2.45 ± 0.66 and 2.77 ± 0.85 in the Varespladib and
placebo groups, respectively (P = 0.36).
CONCLUSIONS: Systemic endothelial function is not reduced after elective PCI
despite eliciting acute inflammatory response. Acute inhibition of sPLA2
activity with Varespladib does not affect endothelial or microvascular function
after PCI.
Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc.
All rights reserved.
DOI: 10.1016/j.cjca.2011.11.007
PMID: 22281412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19697278 | 1. IDrugs. 2009 Sep;12(9):585-92.
Varespladib methyl, an oral phospholipase A2 inhibitor for the potential
treatment of coronary artery disease.
Karakas M(1), Koenig W.
Author information:
(1)University of Ulm Medical Center, Department of Internal Medicine
II-Cardiology, Albert-Einstein Allee 23, D-89081 Ulm, Germany.
Varespladib methyl is an oral secretory phospholipase A2 inhibitor that is being
developed by Anthera Pharmaceuticals Inc for the potential treatment of coronary
artery disease, acute coronary syndrome and inflammation. Varespladib methyl is
a prodrug that is rapidly metabolized to varespladib, and both compounds are
able to potently inhibit the enzymes of the human secretory phospholipase groups
IIa, V and X, which play a pivotal role in atherosclerotic disease and
inflammation. Phase II clinical trials of varespladib methyl in patients with
coronary artery disease, rheumatoid arthritis, asthma and ulcerative colitis
revealed that the drug was well tolerated. Varespladib methyl did not
demonstrate a good efficacy profile in patients with rheumatoid arthritis,
asthma and ulcerative colitis, whereas in patients with coronary artery disease,
varespladib methyl consistently reduced LDL-cholesterol levels (elevated
LDL-cholesterol levels are a marker of increased cardiovascular risk). At the
time of publication, phase II trials were ongoing in patients with acute
coronary syndrome and in patients undergoing elective percutaneous coronary
intervention, and a phase III trial in patients with acute coronary syndrome was
planned. Varespladib methyl could represent a novel therapy for the treatment of
cardiovascular disease, although the efficacy, safety profile and advantages of
this drug compared with existing therapeutic options would need to be
established in upcoming phase III trials.
PMID: 19697278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22446440 | 1. J Craniofac Surg. 2012 Mar;23(2):e115-7. doi: 10.1097/SCS.0b013e31824cd9f6.
Muenke syndrome associated with multiple osteochondromas.
Talbot SG(1), Upton J, Rogers GF.
Author information:
(1)Department of Plastic Surgery, Children's Hospital Boston and Harvard Medical
School, Boston, Massachusetts, USA.
Muenke syndrome caused by the FGFR3 Pro250Arg mutation is associated with
craniosynostosis, hearing loss, and various bony anomalies. Although this
mutation is involved in bone growth and development, bony tumors are rare in
this condition. We describe a patient with a molecular diagnosis of Muenke
syndrome who also presented with multiple osteochondromas of the upper and lower
extremities. This association has only been described once before in a patient
with an isolated osteochondroma of the proximal tibia. Altered expression of
FGFR3, an important mediator of chondrocyte proliferation and differentiation
during in the growth plates of long bones, may help to explain the development
of osteochondromatous lesions in this patient.
DOI: 10.1097/SCS.0b013e31824cd9f6
PMID: 22446440 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24964723 | 1. Br J Clin Pharmacol. 2014 Dec;78(6):1407-18. doi: 10.1111/bcp.12453.
Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2
(SGLT2) inhibitor, in patients with type 2 diabetes.
Riggs MM(1), Seman LJ, Staab A, MacGregor TR, Gillespie W, Gastonguay MR, Woerle
HJ, Macha S.
Author information:
(1)Metrum Research Group LLC, Tariffville, CT.
AIMS: To provide model-based clinical development decision support including
dose selection guidance for empagliflozin, an orally administered sodium glucose
cotransporter 2 inhibitor, through developed exposure-response (E-R) models for
efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM).
METHODS: Five randomized, placebo-controlled, multiple oral dose studies of
empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration ≤12
weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin
[HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two
studies (n = 748, 12 weeks) were used to evaluate tolerability E-R.
RESULTS: The efficacy model predicted maximal decreases in FPG and HbA1c of 16%
and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm
(144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these
maximums. Increases in exposure had no effect on incidence rates of
hypoglycaemia (n = 4), urinary tract infection (n = 17) or
genital/vulvovaginal-related (n = 16) events, although low prevalence rates may
have precluded more accurate evaluation.
CONCLUSIONS: E-R analyses indicated that 10 and 25 mg once daily empagliflozin
doses achieved near maximal glucose lowering efficacy.
© 2014 The British Pharmacological Society.
DOI: 10.1111/bcp.12453
PMCID: PMC4256629
PMID: 24964723 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23334284 | 1. Chromosoma. 2013 Mar;122(1-2):121-34. doi: 10.1007/s00412-013-0396-y. Epub
2013 Jan 20.
An Eco1-independent sister chromatid cohesion establishment pathway in S.
cerevisiae.
Borges V(1), Smith DJ, Whitehouse I, Uhlmann F.
Author information:
(1)Chromosome Segregation Laboratory, Cancer Research UK London Research
Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cohesion between sister chromatids, mediated by the chromosomal cohesin complex,
is a prerequisite for their alignment on the spindle apparatus and segregation
in mitosis. Budding yeast cohesin first associates with chromosomes in G1. Then,
during DNA replication in S-phase, the replication fork-associated
acetyltransferase Eco1 acetylates the cohesin subunit Smc3 to make cohesin's DNA
binding resistant to destabilization by the Wapl protein. Whether stabilization
of cohesin molecules that happen to link sister chromatids is sufficient to
build sister chromatid cohesion, or whether additional reactions are required to
establish these links, is not known. In addition to Eco1, several other factors
contribute to cohesion establishment, including Ctf4, Ctf18, Tof1, Csm3, Chl1
and Mrc1, but little is known about their roles. Here, we show that each of
these factors facilitates cohesin acetylation. Moreover, the absence of Ctf4 and
Chl1, but not of the other factors, causes a synthetic growth defect in cells
lacking Eco1. Distinct from acetylation defects, sister chromatid cohesion in
ctf4Δ and chl1Δ cells is not improved by removing Wapl. Unlike previously
thought, we do not find evidence for a role of Ctf4 and Chl1 in Okazaki fragment
processing, or of Okazaki fragment processing in sister chromatid cohesion.
Thus, Ctf4 and Chl1 delineate an additional acetylation-independent pathway that
might hold important clues as to the mechanism of sister chromatid cohesion
establishment.
DOI: 10.1007/s00412-013-0396-y
PMCID: PMC3608886
PMID: 23334284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24247616 | 1. JAMA. 2014 Jan 15;311(3):252-62. doi: 10.1001/jama.2013.282836.
Varespladib and cardiovascular events in patients with an acute coronary
syndrome: the VISTA-16 randomized clinical trial.
Nicholls SJ(1), Kastelein JJ(2), Schwartz GG(3), Bash D(4), Rosenson RS(5),
Cavender MA(6), Brennan DM(4), Koenig W(7), Jukema JW(8), Nambi V(9), Wright
RS(10), Menon V(4), Lincoff AM(4), Nissen SE(4); VISTA-16 Investigators.
Collaborators: Hennekens C, Brown WV, DeMets D, Pfeffer M, Roleau J, Abraham J,
Gebel J, Huff C, Katzan I, Shishehbor M, Rassi A, Uchino K, Vest A, Zishiri E,
Heckman MJ, Balog C, Dart A, Amerena J, Prasad C, Farshid A, Gunalingam B,
Thompson P, Collins N, Arstall M, van Gaal W, Aroney C, Mahar L, Youssef G,
Horowitz J, Anand D, Rodes-Cabau J, Polasek P, Lai C, Huynh T, Hubacek J, Kokis
A, Paradis JM, Mukherjee A, Senaratne M, Constance C, Gosselin G, Lavi S, Parker
J, Zadra R, Abramson B, Della-Siega A, Spinar J, Pudil R, Motovska Z, Maly M,
Hutyra M, Pleva L, Mayer O, Semenka J, Klimovic T, Horak D, Cervinka P, Klimsa
Z, Hulinsky V, Reichert P, Monhart Z, Rotterova H, Kobulia B, Shaburishvili T,
Mamatsashvili M, Chapidze G, Chumburidze V, Megreladze I, Khintibidze I,
Leithäuser B, Voehringer HF, Wachter R, Nogai K, Lapp H, Haltern G, Gielen S,
Dorsel T, Möllmann H, Stellbrink C, Hengstenberg C, Dengler T, Heuer H, Kreuzer
J, Leschke M, Mudra H, Werner N, Braun-Dullaeus R, Rosenberg M, Frey N, Koenig
W, Strasser R, Genth-Zotz S, Kiss R, Nagy A, Kovacs Z, Csapo K, Edes I, Sereg M,
Vertes A, Ronaszeki A, Kancz S, Benczur B, Polgar P, Muller G, Simonyi G, Dezsi
C, Merkely B, Dinnyes J, Lupkovics G, Kahali D, Banker D, Trivedi S, Rajput R,
Premchand R, Dani S, Vadaganelli P, Gupta S, Chandra S, Fulwani M, Chawla K,
Parikh K, Prati F, Speciale G, Valgimigli M, Suriano P, Berni A, Sangiorgi G,
Fineschi M, Merenda R, Marenzi G, Berti S, Corrada E, Cuccia C, Testa R, Moretti
L, Mennuni M, Biasucci LM, Lioy E, Auguadro C, Magagnini E, Fedele F, Piscione
F, Azar R, Trip MD, Liem A, den Hartoog M, Lenderink T, van de Wetering ML, Lok
D, Oei F, Tans JG, Ilmer B, Keijzers M, Monraats P, Kedhi E, Breedveld RW,
Herrman J, van Wijk L, Ronner E, Nierop P, Bosschaert M, Hermans W, Doevendans
P, Troquay R, van der Heijden R, Veen G, Bokern MJ, Bronzwaer PN, Kie SH, Den
Hartog F, Elliott J, Wilkins G, Hart H, Devlin G, Harding S, Ponikowski P, Madej
A, Kochmanski M, Witkowski A, Pluta W, Bronisz M, Kornacewicz-Jach Z, Wysokinski
A, Ujda M, Drozdz J, Derlaga B, Gessek J, Dabrowski M, Miekus P, Kozlowski A,
Gniot J, Musial W, Dobrzycki S, Rynkiewicz A, Psuja P, Rekosz J, Drzewiecki A,
Kuznetsov V, Gordeev I, Goloshchekin B, Markov V, Barbarich V, Belenky D, Mikhin
V, Volkova E, Timofeev A, Ermoshkina L, Barbarash O, Klein G, Libis R,
Vishnevsky A, Linev K, Khaisheva L, Ruda M, Dovgalevskiy Y, Shvarts Y,
Zateyshchikov D, Kostenko V, Shalnev V, Simanenkov V, Arkhipov M, Ovcharenko E,
Guseva G, Akhunova S, Ortiz AI, Navarro MJ, Romero AJ, Goya IL, Peñaranda AS,
Cendon AA, Rubio AM, Zubiri JJ, Soriano FR, Sanz RR, Genís AB, Lago VN,
Fernández JD, Romo AI, Franco SN, Martin IH, Montero JS, Martin Mde M, González
MJ, Antolin JM, Areses EL, Miranda JM, Alonso-Pulpón L, Esquivias GB, Jarne EF,
Cortés JM, Pérez MB, Gormaz CL, Alegret JM, Nava JS, Ingelmo JM, Urbano RH,
Sanmartín M, Katerenchuk O, Vakaliuk I, Karpenko O, Prokhorov O, Koval O, Faynyk
A, Kopytsya M, Karpenko Y, Kraiz I, Feskov O, Rudenko L, Kozhukhov S,
Goloborodko B, Rivera E, Broadwater S, Crowley S, Vijay N, Goswami R, Ferrier L,
Blanchard A, McCullum K, Chernick R, Bertolet B, Battaglia J, Richardson J,
Lochridge S, Lieberman S, Amkieh A, Cavender JB, Denning S, Treasure C, Kmetzo
J, Stillabower M, Brilakis E, Schwartz G, Acheatel R, Kukuy E, Ashchi M,
Skelding K, Martin L, Gillespie E, French W, Pollock S, Polk D, Black R,
Drenning D, Anderson J, Sanz M, Korban E, Wiley M, Rezkalla S, Minisi A, Shah A,
Silverman P, Amlani M, Eaton G, Brown A, Jay D, Loussararian A, Lamas G, Lauer
M, Williams J, Asfour A, Runquist L, Robertson R, Blonder R, Davies C, Downes T,
Chronos N, Marso S, Haldis T, Eich D, Ahmed M, East C, MacDonald L, Seigel P,
White M, Camp A, Kleiman N, Burtt D, Strain J, Go B, Henry P, Sultan P,
Delafontaine P, Kashou H, Lambert C, Movahed M, Saucedo J, Thadani U,
Chandrashekhar Y, Lu D, Chandna H, Mann J, Ramaswamy G, Browne K, Janik M,
Cannon K, Tolerico P.
Author information:
(1)South Australian Health and Medical Research Institute and University of
Adelaide, Adelaide, Australia.
(2)Academic Medical Center, Amsterdam, the Netherlands.
(3)Veterans Affairs Medical Center and University of Colorado, Colorado, Denver.
(4)Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
(5)Icahn School of Medicine at Mount Sinai, New York, New York.
(6)Brigham and Women's Hospital, Boston, Massachusetts.
(7)University of Ulm Medical Center, Ulm, Germany.
(8)Leiden University Medical Center, Leiden, and Interuniversity Cardiology
Institute of the Netherlands, Utrecht, the Netherlands.
(9)Michael E. DeBakey Veterans Affairs Hospital and Baylor College of Medicine,
Houston, Texas.
(10)Mayo Clinic, Rochester, Minnesota.
Comment in
Nat Rev Cardiol. 2014 Mar;11(3):130-2. doi: 10.1038/nrcardio.2013.220.
IMPORTANCE: Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid
products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has
favorable effects on lipid and inflammatory markers; however, its effect on
cardiovascular outcomes is unknown.
OBJECTIVE: To determine the effects of sPLA2 inhibition with varespladib on
cardiovascular outcomes.
DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial
at 362 academic and community hospitals in Europe, Australia, New Zealand,
India, and North America of 5145 patients randomized within 96 hours of
presentation of an acute coronary syndrome (ACS) to either varespladib
(n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March
7, 2012 (study termination on March 9, 2012).
INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or
placebo daily for 16 weeks, in addition to atorvastatin and other established
therapies.
MAIN OUTCOMES AND MEASURES: The primary efficacy measure was a composite of
cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke,
or unstable angina with evidence of ischemia requiring hospitalization at 16
weeks. Six-month survival status was also evaluated.
RESULTS: At a prespecified interim analysis, including 212 primary end point
events, the independent data and safety monitoring board recommended termination
of the trial for futility and possible harm. The primary end point occurred in
136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%)
treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank
P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47
[2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary
end point of cardiovascular mortality, MI, and stroke was observed in 107
patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo
group (HR, 1.36; 95% CI, 1.02-1.82; P = .04).
CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not
reduce the risk of recurrent cardiovascular events and significantly increased
the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not
a useful strategy to reduce adverse cardiovascular outcomes after ACS.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246.
DOI: 10.1001/jama.2013.282836
PMID: 24247616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21844411 | 1. Arch Otolaryngol Head Neck Surg. 2011 Aug;137(8):775-8. doi:
10.1001/archoto.2011.115.
Audiological profile of children and young adults with syndromic and complex
craniosynostosis.
de Jong T(1), Toll MS, de Gier HH, Mathijssen IM.
Author information:
(1)Department of Plastic, Reconstructive, and Hand Surgery, Erasmus Medical
Center-Sophia, Rotterdam, the Netherlands. [email protected]
OBJECTIVES: To determine syndrome-specific type, severity, and prevalence of
hearing loss to facilitate follow-up and treatment.
DESIGN: Tertiary pediatric hospital craniofacial clinic survey study. If
insufficient or no data were available for a child, he or she was referred to an
audiologist for pure-tone audiometry.
SETTING: Academic research facility.
PATIENTS: Information was gathered regarding 132 children and young adults with
craniosynostosis.
MAIN OUTCOME MEASURES: The primary outcome was hearing assessment of children
and young adults with various types of craniosynostosis. A secondary outcome was
inference regarding the incidence of otitis media among children and young
adults with craniosynostosis.
RESULTS: We found mild or moderate hearing loss in 44.0% of patients with Apert
syndrome, in 28.5% with Crouzon syndrome, in 62.1% with Muenke syndrome, in
28.6% with Saethre-Chotzen syndrome, and in 6.7% with complex craniosynostosis.
Hearing loss was conductive in most patients with Apert, Crouzon, and
Saethre-Chotzen syndromes and it was predominantly sensorineural in patients
with Muenke syndrome. Sensorineural hearing loss at lower frequencies was found
only in patients with Muenke syndrome.
CONCLUSIONS: Most patients with syndromic and complex craniosynostosis have
recurrent otitis media with effusion, causing episodes of conductive hearing
loss throughout their lives. Sensorineural hearing loss can occur in all 4
syndromes studied but is the primary cause of hearing loss in children and young
adults with Muenke syndrome. For patients with these syndromes, we recommend
routine visits to the general practitioner or otolaryngologist, depending on
national standards of care, to screen for otitis media with effusion throughout
life. We also advise early screening for sensorineural hearing loss among
children and young adults with these syndromes.
DOI: 10.1001/archoto.2011.115
PMID: 21844411 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20392737 | 1. J Cell Sci. 2010 May 1;123(Pt 9):1414-26. doi: 10.1242/jcs.064931. Epub 2010
Apr 14.
Stepwise evolution of the centriole-assembly pathway.
Carvalho-Santos Z(1), Machado P, Branco P, Tavares-Cadete F, Rodrigues-Martins
A, Pereira-Leal JB, Bettencourt-Dias M.
Author information:
(1)Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, P-2780-156 Oeiras,
Portugal.
The centriole and basal body (CBB) structure nucleates cilia and flagella, and
is an essential component of the centrosome, underlying eukaryotic
microtubule-based motility, cell division and polarity. In recent years,
components of the CBB-assembly machinery have been identified, but little is
known about their regulation and evolution. Given the diversity of cellular
contexts encountered in eukaryotes, but the remarkable conservation of CBB
morphology, we asked whether general mechanistic principles could explain CBB
assembly. We analysed the distribution of each component of the human
CBB-assembly machinery across eukaryotes as a strategy to generate testable
hypotheses. We found an evolutionarily cohesive and ancestral module, which we
term UNIMOD and is defined by three components (SAS6, SAS4/CPAP and
BLD10/CEP135), that correlates with the occurrence of CBBs. Unexpectedly, other
players (SAK/PLK4, SPD2/CEP192 and CP110) emerged in a taxon-specific manner. We
report that gene duplication plays an important role in the evolution of CBB
components and show that, in the case of BLD10/CEP135, this is a source of
tissue specificity in CBB and flagella biogenesis. Moreover, we observe extreme
protein divergence amongst CBB components and show experimentally that there is
loss of cross-species complementation among SAK/PLK4 family members, suggesting
species-specific adaptations in CBB assembly. We propose that the UNIMOD theory
explains the conservation of CBB architecture and that taxon- and
tissue-specific molecular innovations, gained through emergence, duplication and
divergence, play important roles in coordinating CBB biogenesis and function in
different cellular contexts.
DOI: 10.1242/jcs.064931
PMID: 20392737 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21824072 | 1. Recent Pat Antiinfect Drug Discov. 2011 Sep 1;6(3):189-205. doi:
10.2174/157489111796887855.
Current update on eosinophilic lung diseases and anti-IL-5 treatment.
Samitas K(1), Rådinger M, Bossios A.
Author information:
(1)7th Respiratory Department and Asthma Centre, Athens Chest Hospital, Athens,
Greece.
Peripheral blood eosinophilia and eosinophilic lung inflammation are common in a
variety of pulmonary conditions, including eosinophilic pneumonia and asthma,
hypereosinophilic syndrome and Churg-Strauss syndrome. Therapy in most of these
clinical entities consists of long-term treatment with systemic corticosteroids,
which is not always successful and has substantial side-effects. Interest has
increased considerably regarding alternative corticosteroid-sparing "smart"
regimens in these diseases that target IL-5, an important regulator of
eosinophilic development and function. To date, two humanized monoclonal
antibodies, mepolizumab and reslizumab, have been developed that bind to human
IL-5. In addition a new monoclonal antibody (MEDI-563) has been recently
developed targeting the IL-5 receptor. This review will investigate the current
status on IL-5 targeted therapy and related patents regarding eosinophil-driven
respiratory diseases, primarily eosinophilic asthma but also CSS and HES. Recent
advances and information from clinical trials will be presented in a way that
will allow the reader to approach the role of the eosinophil in the lung
diseases presented in this review.
DOI: 10.2174/157489111796887855
PMID: 21824072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23100377 | 1. Clin Chem Lab Med. 2012;50(9):1601-5. doi: 10.1515/cclm-2011-0888.
Interference of the new oral anticoagulant dabigatran with frequently used
coagulation tests.
Halbmayer WM(1), Weigel G, Quehenberger P, Tomasits J, Haushofer AC, Aspoeck G,
Loacker L, Schnapka-Koepf M, Goebel G, Griesmacher A.
Author information:
(1)Institute of Laboratory Medicine, Municipal Hospital Hietzing-Rosenhuegel,
Vienna, Austria. [email protected]
Comment in
Clin Chem Lab Med. 2012 Sep 06;50(9):1501-3. doi: 10.1515/cclm-2012-0143.
BACKGROUND: Dabigatran etexilate is a new oral anticoagulant for the therapy and
prophylaxis of venous thromboembolism and stroke prevention in patients with
atrial fibrillation. To investigate the extent of interactions of this new
anticoagulant with frequently used coagulation assays, we completed a
multicenter in vitro trial with Conformité Européenne(CE)-labeled
dabigatran-spiked plasma samples.
METHODS: Lyophilized plasma samples with dabigatran concentrations ranging from
0.00 to 0.48 μg/mL were sent to the coagulation laboratories of six major
Austrian hospitals for evaluation. Coagulation assays were performed under
routine conditions using standard reagents and analyzer.
RESULTS: Dabigatran led to a dose-dependent prolongation of the clotting times
in coagulometric tests and influenced the majority of the parameters measured.
Statistically significant interference could be observed with the prothrombin
time (PT), activated partial thromboplastin time (aPTT) and PT/aPTT-based assays
(extrinsic/intrinsic factors, APC-resistance test) as well as lupus
anticoagulant testing. Even non-clotting tests, such as the colorimetric factor
XIII activity assay and to a minor extent the amidolytic antithrombin activity
assay (via factor IIa) were affected.
CONCLUSIONS: This multicenter trial confirms and also adds to existing data,
demonstrating that laboratories should expect to observe strong interferences of
coagulation tests with increasing concentrations of dabigatran. This finding
might become particularly important in the elderly and in patients with renal
impairment as well as patients whose blood is drawn at peak levels of
dabigatran.
DOI: 10.1515/cclm-2011-0888
PMID: 23100377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22299802 | 1. J Child Adolesc Psychiatr Nurs. 2012 Feb;25(1):9-16. doi:
10.1111/j.1744-6171.2011.00305.x. Epub 2011 Oct 17.
Externalizing metaphors: anxiety and high-functioning autism.
McGuinty E(1), Armstrong D, Nelson J, Sheeler S.
Author information:
(1)Hands TheFamilyHelpNetwork.ca, Ontario, Canada. [email protected]
TOPIC: The intent of this article is to explore the efficacy of both the literal
and concrete externalization aspects within narrative therapy, and the
implementation of interactive metaphors as a combined psychotherapeutic approach
for decreasing anxiety with people who present with high-functioning autism.
PURPOSE: The purpose of this exploratory article is to propose the use of
externalizing metaphors as a treatment modality as a potentially useful way to
engage clients. Specifically, a three-step process of change is described, which
allows for concretizing affective states and experiences, and makes use of
visual strengths of people presenting with an autism spectrum disorder.
SOURCE: A selective review was conducted of significant works regarding the
process of change in narrative therapy, with particular emphasis on metaphors.
Works were selected based on their relevance to the current paper and included
both published works (searched via Psyc-INFO) and materials from narrative
training sessions.
CONCLUSIONS: Further research is needed to address the testable hypotheses
resulting from the current model. This line of research would not only establish
best practices in a population for which there is no broadly accepted treatment
paradigm, but would also contribute to the larger fields of abnormal psychology,
emotion regulation, and cognitive psychology by further elucidating the complex
ways these systems interact.
© 2011 Wiley Periodicals, Inc.
DOI: 10.1111/j.1744-6171.2011.00305.x
PMID: 22299802 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24227418 | 1. Pediatr Obes. 2015 Feb;10(1):37-44. doi: 10.1111/j.2047-6310.2013.00202.x.
Epub 2013 Nov 13.
Cardiometabolic risk factors and insulin resistance in obese children and
adolescents: relation to puberty.
Tobisch B(1), Blatniczky L, Barkai L.
Author information:
(1)St. John's and North-Buda United Hospitals of Budapest Municipality,
Budapest, Hungary.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The prevalence of obesity with
concomitant increasing risk for having cardiometabolic diseases is rising in the
childhood population. Insulin resistance has a key role in metabolic changes in
these children. Insulin levels elevate as puberty commences in every individual.
WHAT THIS STUDY ADDS: Children with increased risk for cardiometabolic diseases
show significant differences in insulin levels even before the onset of puberty
compared with those without risks. The pattern of appearance of dyslipidaemia
also varies in children with risk factors even in the pre-pubertal group from
those without risk. Children with metabolic syndrome display considerably
pronounced changes in their metabolic parameters before the onset of puberty,
which become more pronounced as puberty passes.
BACKGROUND: Insulin resistance (IR) has a key role in the metabolic changes in
obese children. In commencing puberty, the insulin levels elevate. It is not
clear, however, how insulin levels develop if the metabolic syndrome appears.
OBJECTIVES: Metabolic changes were assessed in obese children before, during and
after puberty to analyse the relationship between IR and puberty in subjects
with and without metabolic syndrome.
METHODS: Three hundred thirty-four obese children (5-19 years) attended the
study. The criteria of the International Diabetes Federation were used to assess
the presence of cardiometabolic risks (CMRs). Subjects with increased CMR were
compared with those without risk (nCMR). Pubertal staging, lipid levels, plasma
glucose and insulin levels during oral glucose tolerance test were determined in
each participant. IR was expressed by homeostasis model assessment (HOMA-IR) and
the ratio of glucose and insulin areas under the curve (AUC-IR).
RESULTS: Significantly higher AUC-IR were found in pre-pubertal CMR children
compared with nCMR subjects (11.84 ± 1.03 vs. 8.00 ± 0.69; P < 0.01), but no
difference was discovered during and after puberty. HOMA-IR differs between CMR
and nCMR only in post-puberty (6.03 ± 1.26 vs. 2.54 ± 0.23; P < 0.01). CMR
children have dyslipidaemia before the onset of puberty.
CONCLUSIONS: CMR is associated with increased postprandial IR in pre-pubertal
and increased fasting IR in post-pubertal obese children. Dyslipidaemia appeared
already in pre-puberty in CMR children.
© 2013 The Authors. Pediatric Obesity © 2013 International Association for the
Study of Obesity.
DOI: 10.1111/j.2047-6310.2013.00202.x
PMID: 24227418 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26028407 | 1. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015
May 31.
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
Brahmer J(1), Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia
S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén
Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L,
Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR.
Author information:
(1)From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,
Baltimore (J.B.); the City of Hope Comprehensive Cancer Center, Duarte, CA
(K.L.R.); the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital,
Amsterdam (P.B.), Erasmus MC Cancer Institute, Rotterdam (J.G.A.), and
Ziekenhuis Amphia, Breda (J.G.A.) - all in the Netherlands; the University
Hospital of Perugia, Perugia (L.C.), and the Fondazione IRCCS Istituto Nazionale
dei Tumori, Milan (M.C.G.) - both in Italy; the Department of Medical Oncology,
West German Cancer Center, Universitätsklinikum Essen, and the Ruhrlandklinik,
Universität Duisburg-Essen, Essen (W.E.E.E.), the Thoraxklinik, Heidelberg
University Hospital, Heidelberg (M.S.), and the LungenClinic Grosshansdorf,
Grosshansdorf (M.R.) - all in Germany; the N.N. Blokhin Russian Cancer Research
Center, Moscow (E.P.); the H. Lee Moffitt Cancer Center and Research Institute,
Tampa, FL (S.A.); the Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie,
Warsaw, Poland (A.P.); the University of Chicago Medicine and Biological
Sciences, Chicago (E.E.V.); the Hospital Madrid Norte Sanchinarro (E.H.), the
Hospital Universitario Fundación Jiménez Díaz, Madrid (M.D.), and the Hospital
Universitario Virgen Del Rocío, Seville (L.P.-A.) - all in Spain; Oncology
Hematology Care, Cincinnati (D.W.); the Duke University Medical Center, Durham,
NC (N.R.); Massachusetts General Hospital, Boston (J.G.); Centro Internacional
de Estudios Clinicos, Santiago, Chile (O.A.F.); Nemocnice Na Bulovce, Prague,
Czech Republic (L.H.); Bristol-Myers Squibb, Princeton, NJ (C.B., C.T.H., B.L.);
and the Sarah Cannon Research Institute and Tennessee Oncology, Nashville
(D.R.S.).
Comment in
Nat Rev Clin Oncol. 2015 Aug;12(8):436. doi: 10.1038/nrclinonc.2015.110.
BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer
(NSCLC) who have disease progression during or after first-line chemotherapy
have limited treatment options. This randomized, open-label, international,
phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4
programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with
docetaxel in this patient population.
METHODS: We randomly assigned 272 patients to receive nivolumab, at a dose of 3
mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg
per square meter of body-surface area every 3 weeks. The primary end point was
overall survival.
RESULTS: The median overall survival was 9.2 months (95% confidence interval
[CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with
docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel
(hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall
survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17
to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with
docetaxel (P=0.008). The median progression-free survival was 3.5 months with
nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease
progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1
ligand (PD-L1) was neither prognostic nor predictive of benefit.
Treatment-related adverse events of grade 3 or 4 were reported in 7% of the
patients in the nivolumab group as compared with 55% of those in the docetaxel
group.
CONCLUSIONS: Among patients with advanced, previously treated squamous-cell
NSCLC, overall survival, response rate, and progression-free survival were
significantly better with nivolumab than with docetaxel, regardless of PD-L1
expression level. (Funded by Bristol-Myers Squibb; CheckMate 017
ClinicalTrials.gov number, NCT01642004.).
DOI: 10.1056/NEJMoa1504627
PMCID: PMC4681400
PMID: 26028407 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24275748 | 1. Autophagy. 2014 Feb;10(2):356-71. doi: 10.4161/auto.26864. Epub 2013 Nov 21.
Characterization of early autophagy signaling by quantitative phosphoproteomics.
Rigbolt KT(1), Zarei M(1), Sprenger A(2), Becker AC(1), Diedrich B(1), Huang
X(3), Eiselein S(4), Kristensen AR(5), Gretzmeier C(1), Andersen JS(6), Zi Z(3),
Dengjel J(7).
Author information:
(1)Freiburg Institute for Advanced Studies (FRIAS); School of Life
Sciences-LifeNet; Freiburg, Germany; ZBSA Center for Biological Systems
Analysis; University of Freiburg; Freiburg, Germany.
(2)Freiburg Institute for Advanced Studies (FRIAS); School of Life
Sciences-LifeNet; Freiburg, Germany; ZBSA Center for Biological Systems
Analysis; University of Freiburg; Freiburg, Germany; Department of Dermatology;
University Freiburg Medical Center; Freiburg, Germany.
(3)BIOSS Centre for Biological Signaling Studies; University of Freiburg;
Freiburg, Germany.
(4)Freiburg Institute for Advanced Studies (FRIAS); School of Life
Sciences-LifeNet; Freiburg, Germany; ZBSA Center for Biological Systems
Analysis; University of Freiburg; Freiburg, Germany; BIOSS Centre for Biological
Signaling Studies; University of Freiburg; Freiburg, Germany.
(5)Centre for High-throughput Biology; Department of Biochemistry and Molecular
Biology; University of British Columbia; Vancouver, BC CA.
(6)Department of Biochemistry and Molecular Biology; University of Southern
Denmark; Odense, Denmark.
(7)Freiburg Institute for Advanced Studies (FRIAS); School of Life
Sciences-LifeNet; Freiburg, Germany; ZBSA Center for Biological Systems
Analysis; University of Freiburg; Freiburg, Germany; Department of Dermatology;
University Freiburg Medical Center; Freiburg, Germany; BIOSS Centre for
Biological Signaling Studies; University of Freiburg; Freiburg, Germany.
Under conditions of nutrient shortage autophagy is the primary cellular
mechanism ensuring availability of substrates for continuous biosynthesis.
Subjecting cells to starvation or rapamycin efficiently induces autophagy by
inhibiting the MTOR signaling pathway triggering increased autophagic flux. To
elucidate the regulation of early signaling events upon autophagy induction, we
applied quantitative phosphoproteomics characterizing the temporal
phosphorylation dynamics after starvation and rapamycin treatment. We obtained a
comprehensive atlas of phosphorylation kinetics within the first 30 min upon
induction of autophagy with both treatments affecting widely different cellular
processes. The identification of dynamic phosphorylation already after 2 min
demonstrates that the earliest events in autophagy signaling occur rapidly after
induction. The data was subjected to extensive bioinformatics analysis revealing
regulated phosphorylation sites on proteins involved in a wide range of cellular
processes and an impact of the treatments on the kinome. To approach the
potential function of the identified phosphorylation sites we performed a screen
for MAP1LC3-interacting proteins and identified a group of binding partners
exhibiting dynamic phosphorylation patterns. The data presented here provide a
valuable resource on phosphorylation events underlying early autophagy
induction.
DOI: 10.4161/auto.26864
PMCID: PMC5396084
PMID: 24275748 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21919012 | 1. Clin Cardiol. 2011 Nov;34(11):672-6. doi: 10.1002/clc.20957. Epub 2011 Sep 14.
Cardiac rupture in takotsubo cardiomyopathy: a systematic review.
Kumar S(1), Kaushik S, Nautiyal A, Choudhary SK, Kayastha BL, Mostow N, Lazar
JM.
Author information:
(1)Department of Cardiovascular Medicine, SUNY Downstate Medical Center,
Brooklyn, New York 11203, USA. [email protected]
Comment in
Clin Cardiol. 2011 Nov;34(11):651-2. doi: 10.1002/clc.20971.
BACKGROUND: Takotsubo cardiomyopathy (TSC) and its complications, such as
cardiac rupture (CR), are increasingly being reported in the literature. CR is
associated with rapid clinical decline and is uniformly fatal if not surgically
repaired. To identify patients who developed CR we performed an analysis of all
available indexed cases in the literature and compared them with a control group
of patients with TSC without rupture.
HYPOTHESIS: Takotsubo cardiomyopathy patients with cardiac rupture do not differ
significantly from those without rupture.
METHODS: MEDLINE (2009) was searched for all TSC case reports with CR. Eleven
case reports were identified. Using a random sampling method, we selected 12
case reports of TSC without rupture (control). We included our patient with TSC
with rupture as the 12th case of TSC cohort with CR (CR group). Demographic and
clinical characteristics were compared between CR group and control.
RESULTS: All patients in the TSC group with rupture were female and were
significantly older than controls. TSC group with rupture had significantly
higher frequency of ST elevation in lead II and absence of T-wave inversion in
lead V5 on hospital admission than controls. Mean ejection fraction, systolic
blood pressure, and double product, a measure of oxygen demand, was
significantly higher in the rupture group compared to controls. The CR group was
associated with less frequent use of β-blocker as compared to controls.
CONCLUSIONS: CR as a complication of TSC could be more common than recognized.
Higher double product and ejection fraction suggest higher fluctuation of
intracardiac pressure and may cause CR in TSC. Use of β blockers in TSC may
provide protection against CR.
© 2011 Wiley Periodicals, Inc.
DOI: 10.1002/clc.20957
PMCID: PMC6652409
PMID: 21919012 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23150908 | 1. N Engl J Med. 2013 Jan 10;368(2):107-16. doi: 10.1056/NEJMoa1211103. Epub 2012
Nov 14.
Variant of TREM2 associated with the risk of Alzheimer's disease.
Jonsson T(1), Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J,
Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I,
Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A,
Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K.
Author information:
(1)deCODE Genetics, Reykjavik, Iceland.
Comment in
N Engl J Med. 2013 Jan 10;368(2):182-4. doi: 10.1056/NEJMe1213157.
Nat Rev Neurol. 2013 Jan;9(1):5. doi: 10.1038/nrneurol.2012.254.
Clin Genet. 2013 Jun;83(6):525-6. doi: 10.1111/cge.12108.
N Engl J Med. 2013 Oct 17;369(16):1568-9. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1564-5. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1565. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1568. doi: 10.1056/NEJMc1306509.
BACKGROUND: Sequence variants, including the ε4 allele of apolipoprotein E, have
been associated with the risk of the common late-onset form of Alzheimer's
disease. Few rare variants affecting the risk of late-onset Alzheimer's disease
have been found.
METHODS: We obtained the genome sequences of 2261 Icelanders and identified
sequence variants that were likely to affect protein function. We imputed these
variants into the genomes of patients with Alzheimer's disease and control
participants and then tested for an association with Alzheimer's disease. We
performed replication tests using case-control series from the United States,
Norway, The Netherlands, and Germany. We also tested for a genetic association
with cognitive function in a population of unaffected elderly persons.
RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the
triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to
result in an R47H substitution, was found to confer a significant risk of
Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI],
2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls
85 years of age or older. We observed the association in additional sample sets
(odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and
replication samples). We also found that carriers of rs75932628-T between the
ages of 80 and 100 years without Alzheimer's disease had poorer cognitive
function than noncarriers (P=0.003).
CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis
of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the
brain, the R47H substitution may lead to an increased predisposition to
Alzheimer's disease through impaired containment of inflammatory processes.
(Funded by the National Institute on Aging and others.).
DOI: 10.1056/NEJMoa1211103
PMCID: PMC3677583
PMID: 23150908 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19913425 | 1. Curr Biol. 2009 Dec 1;19(22):1943-9. doi: 10.1016/j.cub.2009.09.062. Epub 2009
Nov 12.
The amino-terminal TPR domain of Dia2 tethers SCF(Dia2) to the replisome
progression complex.
Morohashi H(1), Maculins T, Labib K.
Author information:
(1)Cancer Research UK Paterson Institute for Cancer Research, University of
Manchester, UK.
Eukaryotic cells contain multiple versions of the E3 ubiquitin ligase known as
the SCF (Skp1/cullin/F box), each of which is distinguished by a different F box
protein that uses a domain at the carboxyl terminus to recognize substrates [1,
2]. The F box protein Dia2 is an important determinant of genome stability in
budding yeast [3-5], but its mode of action is poorly understood. Here we show
that SCF(Dia2) associates with the replisome progression complex (RPC) that
assembles around the MCM2-7 helicase at DNA replication forks [6]. This
interaction requires the RPC components Mrc1 and Ctf4, both of which associate
with a tetratricopeptide repeat (TPR) domain located at the amino terminus of
Dia2. Our data indicate that the TPR domain of Dia2 tethers SCF(Dia2) to the
RPC, probably increasing the local concentration of the ligase at DNA
replication forks. This regulation becomes important in cells that accumulate
stalled DNA replication forks at protein-DNA barriers, perhaps aiding the
interaction of SCF(Dia2) with key substrates. Our findings suggest that the
amino-terminal domains of other F box proteins might also play an analogous
regulatory role, controlling the localization of the cognate SCF complexes.
DOI: 10.1016/j.cub.2009.09.062
PMID: 19913425 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23398530 | 1. Diabetes Obes Metab. 2013 Aug;15(8):721-8. doi: 10.1111/dom.12081. Epub 2013
Mar 4.
A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor
empagliflozin in patients with type 2 diabetes.
Ferrannini E(1), Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ.
Author information:
(1)Department of Internal Medicine, University of Pisa, Pisa, Italy.
[email protected]
AIM: This Phase IIb, randomized, double-blind, placebo-controlled trial
evaluated the efficacy, safety, tolerability and pharmacokinetics of
empagliflozin in patients with type 2 diabetes.
METHODS: Four hundred and eight patients (treatment-naïve or after a 4-week
wash-out period) were randomized to receive empagliflozin 5, 10 or 25 mg once
daily, placebo or open-label metformin for 12 weeks. The primary endpoint was
change in haemoglobin A1c (HbA1c) after 12 weeks.
RESULTS: After 12 weeks' treatment, empagliflozin showed dose-dependent
reductions in HbA1c from baseline [5 mg: -0.4%, 10 mg: -0.5%, 25 mg: -0.6%; all
doses p < 0.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased
with empagliflozin [5 mg: -1.29 mmol/l, 10 mg: -1.61 mmol/l, 25 mg:
-1.72 mmol/l; all doses p < 0.0001 vs. placebo (+0.04 mmol/l)]. Body weight
decreased in all empagliflozin groups (all doses p < 0.001 vs. placebo). The
incidence of adverse events (AEs) was similar in the placebo (32.9%) and
empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin
were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and
nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract
infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one
(1.2%) on placebo. Genital infections were reported in five (2%) patients on
empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature
discontinuation.
CONCLUSIONS: In patients with type 2 diabetes, empagliflozin resulted in
dose-dependent, clinically meaningful reductions in HbA1c and FPG, and
reductions in body weight compared with placebo. Empagliflozin was
well-tolerated with a favourable safety profile.
© 2013 Blackwell Publishing Ltd.
DOI: 10.1111/dom.12081
PMID: 23398530 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24131573 | 1. Reproduction. 2013 Nov 20;147(1):73-80. doi: 10.1530/REP-13-0386. Print 2014
Jan.
AKT is involved in granulosa cell autophagy regulation via mTOR signaling during
rat follicular development and atresia.
Choi J(1), Jo M, Lee E, Choi D.
Author information:
(1)Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical
Center, Sungkyunkwan University School of Medicine.
In this study, we examined whether granulosa cell autophagy during follicular
development and atresia was regulated by the class I phosphoinositide-3
kinase/protein kinase B (AKT) pathway, which is known to control the activity of
mammalian target of rapamycin (mTOR), a major negative regulator of autophagy.
Ovaries and granulosa cells were obtained using an established
gonadotropin-primed immature rat model that induces follicular development and
atresia. Autophagy was evaluated by measuring the expression level of
microtubule-associated protein light chain 3-II (LC3-II) using western blots and
immunohistochemistry. The activity of AKT and mTOR was also examined by
observing the phosphorylation of AKT and ribosomal protein S6 kinase (S6K)
respectively. After gonadotropin injection, LC3-II expression was suppressed and
phosphorylation of AKT and S6K increased in rat granulosa cells. By contrast,
gonadotropin withdrawal by metabolic clearance promoted LC3-II expression and
decreased phosphorylation of AKT and S6K. In addition, in-vitro FSH treatment of
rat granulosa cells also indicated inhibition of LC3-II expression accompanied
by a marked increase in phosphorylation of AKT and S6K. Inhibition of AKT
phosphorylation using AKT inhibitor VIII suppressed FSH-mediated phosphorylation
of S6K, followed by an increase in LC3-II expression. Furthermore, co-treatment
with FSH and AKT inhibitor increased the levels of apoptosis and cell death of
granulosa cells compared with the single treatment with FSH. Taken together, our
findings indicated that AKT-mediated activation of mTOR suppresses granulosa
cell autophagy during follicular development and is involved in the regulation
of apoptotic cell death.
DOI: 10.1530/REP-13-0386
PMID: 24131573 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18949097 | 1. Open Cardiovasc Med J. 2008;2:36-40. doi: 10.2174/1874192400802010036. Epub
2008 Jun 5.
The ability of heart failure specialists to accurately predict NT-proBNP levels
based on clinical assessment and a previous NT-proBNP measurement.
Sedlak TL(1), Chandavimol M, Calleja A, Clark C, Edmonds M, Pu A, Humphries KH,
Ignaszewski A.
Author information:
(1)University of British Columbia.
BACKGROUND: The value of routine aminoterminal pro type B natriuretic peptide
(NT-proBNP) measurements in outpatient clinics remains unknown.
OBJECTIVES: We sought to determine the accuracy with which heart failure (HF)
specialists can predict NT-proBNP levels in HF outpatients based on clinical
assessment.
METHODS: We prospectively studied 160 consecutive HF patients followed in an
outpatient multidisciplinary HF clinic. During a regular office visit, HF
specialists were asked to estimate a patient's current NT-proBNP level based
upon their clinical assessment and all available information from their chart,
including a previous NT-proBNP level (if available). NT-proBNP estimations were
grouped into prognostic categories (<125, 125-1000, 1000-4998, or >/=4999 pg/mL)
and comparisons made between actual and estimate values.
RESULTS: Overall, HF specialists estimated 67.5% of NT-proBNP levels correctly.
After adjusting for clinical characteristics, knowledge of a prior NT-proBNP
measurement was the only significant predictor of estimation accuracy (p=0.01).
Compared to patients with a prior NT-proBNP level <125 pg/mL, physicians were
95% less likely to get a correct estimation in patients with the highest prior
NT-proBNP level (>/=4999 pg/mL).
CONCLUSION: HF specialists are reasonably accurate at estimating current
NT-proBNP levels based upon clinical assessment and a previous NT-proBNP level,
if those levels were < 4999 pg/mL. Likely, initial but not routine NT-proBNP
measurements are useful in outpatient HF clinics.
DOI: 10.2174/1874192400802010036
PMCID: PMC2570572
PMID: 18949097 |
http://www.ncbi.nlm.nih.gov/pubmed/22898782 | 1. Dev Cell. 2012 Aug 14;23(2):412-24. doi: 10.1016/j.devcel.2012.06.001.
BLD10/CEP135 is a microtubule-associated protein that controls the formation of
the flagellum central microtubule pair.
Carvalho-Santos Z(1), Machado P, Alvarez-Martins I, Gouveia SM, Jana SC, Duarte
P, Amado T, Branco P, Freitas MC, Silva ST, Antony C, Bandeiras TM,
Bettencourt-Dias M.
Author information:
(1)Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras,
Portugal. [email protected]
Cilia and flagella are involved in a variety of processes and human diseases,
including ciliopathies and sterility. Their motility is often controlled by a
central microtubule (MT) pair localized within the ciliary MT-based skeleton,
the axoneme. We characterized the formation of the motility apparatus in detail
in Drosophila spermatogenesis. We show that assembly of the central MT pair
starts prior to the meiotic divisions, with nucleation of a singlet MT within
the basal body of a small cilium, and that the second MT of the pair only
assembles much later, upon flagella formation. BLD10/CEP135, a conserved player
in centriole and flagella biogenesis, can bind and stabilize MTs and is required
for the early steps of central MT pair formation. This work describes a
genetically tractable system to study motile cilia formation and provides an
explanation for BLD10/CEP135's role in assembling highly stable MT-based
structures, such as motile axonemes and centrioles.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.devcel.2012.06.001
PMID: 22898782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24278483 | 1. PLoS One. 2013 Nov 22;8(11):e82481. doi: 10.1371/journal.pone.0082481.
eCollection 2013.
The contribution of lysosomotropism to autophagy perturbation.
Ashoor R(1), Yafawi R, Jessen B, Lu S.
Author information:
(1)Drug Safety Research and Development, Pfizer Inc., San Diego, California,
United States of America.
Autophagy refers to the catabolic process in eukaryotic cells that delivers
cytoplasmic material to lysosomes for degradation. This highly conserved process
is involved in the clearance of long-lived proteins and damaged organelles.
Consequently, autophagy is important in providing nutrients to maintain cellular
function under starvation, maintaining cellular homeostasis, and promoting cell
survival under certain conditions. Several pathways, including mTOR, have been
shown to regulate autophagy. However, the impact of lysosomal function
impairment on the autophagy process has not been fully explored. Basic
lipophilic compounds can accumulate in lysosomes via pH partitioning leading to
perturbation of lysosomal function. Our hypothesis is that these types of
compounds can disturb the autophagy process. Eleven drugs previously shown to
accumulate in lysosomes were selected and evaluated for their effects on
cytotoxicity and autophagy using ATP depletion and LC3 assessment, respectively.
All eleven drugs induced increased staining of endogenous LC3 and exogenous
GFP-LC3, even at non toxic dose levels. In addition, an increase in the
abundance of SQSTM1/p62 by all tested compounds denotes that the increase in LC3
is due to autophagy perturbation rather than enhancement. Furthermore, the gene
expression profile resulting from in vitro treatment with these drugs revealed
the suppression of plentiful long-lived proteins, including structural
cytoskeletal and associated proteins, and extracellular matrix proteins. This
finding indicates a retardation of protein turnover which further supports the
notion of autophagy inhibition. Interestingly, upregulation of genes containing
antioxidant response elements, e.g. glutathione S transferase and NAD(P)H
dehydrogenase quinone 1 was observed, suggesting activation of Nrf2
transcription factor. These gene expression changes could be related to an
increase in SQSTM1/p62 resulting from autophagy deficiency. In summary, our data
indicate that lysosomal accumulation due to the basic lipophilic nature of
xenobiotics could be a general mechanism contributing to the perturbation of the
autophagy process.
DOI: 10.1371/journal.pone.0082481
PMCID: PMC3838419
PMID: 24278483 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: All authors are employed by
Pfizer Inc, however this does not alter the authors' adherence to all the PLOS
ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/11164037 | 1. Gene. 2000 Dec 30;261(1):53-62. doi: 10.1016/s0378-1119(00)00480-7.
DNA G+C content of the third codon position and codon usage biases of human
genes.
Sueoka N(1), Kawanishi Y.
Author information:
(1)University of Colorado, Department of Molecular, Cellular, and Developmental
Biology, Boulder, CO 80309-0347, USA. [email protected]
The human genome, as in other eukaryotes, has a wide heterogeneity in the DNA
base composition. The evolutionary basis for this heterogeneity has been
unknown. A previous study of the human genome (846 genes analyzed) has shown
that, in the major range of the G+C content in the third codon position
(0.25-0.75), biases from the Parity Rule 2 (PR2) among the synonymous codons of
the four-codon amino acids are similar except in the highest G+C range (Sueoka,
N., 1999. Translation-coupled violation of Parity Rule 2 in human genes is not
the cause of heterogeneity of the DNA G+C content of third codon position. Gene
238, 53-58.). PR2 is an intra-strand rule where A=T and G=C are expected when
there are no biases between the two complementary strands of DNA in mutation and
selection rates (substitution rates). In this study, 14,026 human genes were
analyzed. In addition, the third codon positions of two-codon amino acids were
analyzed. New results show the following: (a) The G+C contents of the third
codon position of human genes are scattered in the G+C range of 0.22-0.96 in the
third codon position. (b) The PR2 biases are similar in the range of 0.25-0.75,
whereas, in the high G+C range (0.75-0.96; 13% of the genes), the PR2-bias
fingerprints are different from those of the major range. (c) Unlike the PR2
biases, the G+C contents of the third codon position for both four-codon and
two-codon amino acids are all correlated almost perfectly with the G+C content
of the third codon position over the total G+C ranges. These results support the
notion that the directional mutation pressure, rather than the directional
selection pressure, is mainly responsible for the heterogeneity of the G+C
content of the third codon position.
DOI: 10.1016/s0378-1119(00)00480-7
PMID: 11164037 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11456308 | 1. Ann Neurol. 2001 Jul;50(1):42-6. doi: 10.1002/ana.1033.
Diagnosis of X-linked myotubular myopathy by detection of myotubularin.
Laporte J(1), Kress W, Mandel JL.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire,
CNRS/INSERM/ULP, Strasbourg, France.
Mutations in the MTM1 gene cause X-linked recessive myotubular myopathy (XLMTM;
MIM310400). Myotubularin, the implicated protein, is a phosphoinositide
phosphatase that belongs to a large protein family conserved through evolution
that also includes the antiphosphatase Sbfl and the protein hMTMR2 mutated in
Charcot-Marie-Tooth type 4B. Myotubularin is detectable in a variety of cell
lines by immunoprecipitation followed by Western blotting. We screened 29
independant patients with XLMTM phenotype and four with centronuclear myopathy.
87% (21/24) of patients with known MTM1 mutations showed abnormal myotubularin
levels, including some with missense mutations. Moreover, myotubularin was also
undetectable in a patient for whom no mutation could be identified by SSCP
screening. The centronuclear cases investigated have a normal level of protein,
suggesting that the centronuclear form is not the result of a decrease in
myotubularin level. Thus, immunoprecipitation of myotubularin from cultured
cells represents a rapid and helpful method for classifying those cases where no
mutation was found. On the other hand, the amount of expression may be of
diagnostic value for disease course in patients with a mutation.
DOI: 10.1002/ana.1033
PMID: 11456308 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8015613 | 1. Nature. 1994 Jul 7;370(6484):75-7. doi: 10.1038/370075a0.
Phosphorylation of RNA polymerase II C-terminal domain and transcriptional
elongation.
O'Brien T(1), Hardin S, Greenleaf A, Lis JT.
Author information:
(1)Section of Biochemistry, Molecular and Cell Biology, Cornell University,
Ithaca, New York 14853.
The carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II is
essential in vivo, and is found in either an unphosphorylated (IIa) or
hyperphosphorylated (IIo) form. The Drosophila uninduced hsp70 and hsp26 genes,
and the constitutively expressed beta-1 tubulin and Gapdh-2 genes, contain an
RNA polymerase II complex which pauses after synthesizing a short transcript. We
report here that, using an in vivo ultraviolet crosslinking technique and
antibodies directed against the IIa and IIo forms of the CTD, these paused
polymerases have an unphosphorylated CTD. For genes containing a 5' paused
polymerase, passage of the paused RNA polymerase into an elongationally
competent mode in vivo coincides with phosphorylation of the CTD. Also, the
level of phosphorylation of the CTD of elongating polymerases is shown not to be
related to the level of transcription, but is promoter specific.
DOI: 10.1038/370075a0
PMID: 8015613 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11252143 | 1. Curr Pain Headache Rep. 2001 Feb;5(1):83-91. doi: 10.1007/s11916-001-0015-0.
Treatment and management of cluster headache.
Dodick DW(1), Capobianco DJ.
Author information:
(1)Department of Neurology, Mayo Clinic, 13400 E Shea Boulevard, Scottsdale, AZ
85259, USA. [email protected]
Cluster headache is an uncommon yet well-defined neurovascular syndrome
occurring in both episodic and chronic varieties. The most striking feature of
cluster headache is the unmistakable circadian and circannual periodicity.
Inheritance may play a role in some families. The attacks are of extreme
intensity, of short duration, occur unilaterally, and are accompanied by signs
and symptoms of autonomic dysfunction. In contrast to migraine, during an attack
the cluster patient prefers to pace about. Attacks frequently occur at night.
Although the pathophysiology of cluster headache remains to be fully elucidated,
several seminal observations have recently been made. The medical treatment of
cluster headache includes both acute therapy aimed at aborting individual
attacks and prophylactic therapy aimed at preventing recurrent attacks during
the cluster period. Agents used for acute therapy include inhalation of oxygen,
sumatriptan, and dihydroergotamine. Transitional prophylaxis involves the
short-term use of either corticosteroids or ergotamine derivatives. The
cornerstone of maintenance prophylaxis is verapamil, yet methysergide, lithium,
and divalproex sodium may also be employed. In some patients, melatonin or
topiramate may be useful adjunctive therapies.
DOI: 10.1007/s11916-001-0015-0
PMID: 11252143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15788569 | 1. Mol Biol Cell. 2005 Jun;16(6):2947-59. doi: 10.1091/mbc.e04-10-0914. Epub 2005
Mar 23.
The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and
enhances filopodia formation and motility in macrophages.
Chitu V(1), Pixley FJ, Macaluso F, Larson DR, Condeelis J, Yeung YG, Stanley ER.
Author information:
(1)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY 10461, USA.
Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to
the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of
actin-based functions including cell adhesion and motility. In mouse
macrophages, MAYP is tyrosine phosphorylated after activation of the
colony-stimulating factor-1 receptor (CSF-1R), which also induces actin
reorganization, membrane ruffling, cell spreading, polarization, and migration.
Because MAYP associates with F-actin, we investigated the function of MAYP in
regulating actin organization in macrophages. Overexpression of MAYP decreased
CSF-1-induced membrane ruffling and increased filopodia formation, motility and
CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced
expression of MAYP, indicating that MAYP is a negative regulator of
CSF-1-induced membrane ruffling and positively regulates formation of filopodia
and directional migration. Overexpression of MAYP led to a reduction in total
macrophage F-actin content but was associated with increased actin bundling.
Consistent with this, purified MAYP bundled F-actin and regulated its turnover
in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in
vivo. Because filopodia are postulated to increase directional motility by
acting as environmental sensors, the MAYP-stimulated increase in directional
movement may be at least partly explained by enhancement of filopodia formation.
DOI: 10.1091/mbc.e04-10-0914
PMCID: PMC1142438
PMID: 15788569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22857835 | 1. Pediatr Clin North Am. 2012 Aug;59(4):881-96. doi: 10.1016/j.pcl.2012.05.009.
Epub 2012 Jun 15.
Urolithiasis in children: medical approach.
Copelovitch L(1).
Author information:
(1)Division of Nephrology, Department of Pediatrics, The Children's Hospital of
Philadelphia, Philadelphia, PA 19104, USA. [email protected]
Childhood urolithiasis is an evolving condition with an increasing incidence and
prevalence over the last 2 decades. Over that time the underlying cause has
shifted from predominantly infectious to metabolic in nature. This review
describes the pathophysiology, underlying metabolic abnormalities, clinical
presentation, evaluation, and management of childhood urolithiasis. A
comprehensive metabolic evaluation is essential for all children with renal
calculi, given the high rate of recurrence and the importance of excluding
inherited progressive conditions.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pcl.2012.05.009
PMCID: PMC3426770
PMID: 22857835 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15040183 | 1. Nat Rev Microbiol. 2003 Oct;1(1):75-80. doi: 10.1038/nrmicro736.
Discovering viroids--a personal perspective.
Diener TO(1).
Author information:
(1)University of Maryland Biotechnology Institute, College Park, Maryland 20742,
USA. [email protected]
During 1970 and 1971, I discovered that a devastating disease of potato plants
is not caused by a virus, as had been assumed, but by a new type of subviral
pathogen, the viroid. Viroids are so small--one fiftieth of the size of the
smallest viruses--that many scientists initially doubted their existence. We now
know that viroids cause many damaging diseases of crop plants. Fortunately, new
methods that are based on the unique properties of viroids now promise effective
control.
DOI: 10.1038/nrmicro736
PMID: 15040183 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23833797 | 1. ML346: A Novel Modulator of Proteostasis for Protein Conformational Diseases.
Calamini B(1), Silva MC(1)(2), Madoux F(3), Hutt DM(4), Khanna S(5), Chalfant
MA(4), Allais C(6), Ouizem S(6), Saldanha SA(3), Ferguson J(3), Mercer BA(3),
Michael C(7), Tait BD(5), Garza D(5), Balch WE(4), Roush WR(6), Morimoto RI(1),
Hodder P(3).
In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda
(MD): National Center for Biotechnology Information (US); 2010–.
2012 Dec 17 [updated 2013 Apr 5].
Author information:
(1)Department of Molecular Biosciences, Rice Institute for Biomedical Research,
Northwestern University, Evanston, IL, USA
(2)Faculty of Sciences, Centre for Biodiversity, Functional and Integrative
Genomics; (BioFIG), University of Lisboa, Lisboa, Portugal
(3)Scripps Research Institute Molecular Screening Center, Lead Identification
Division, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA
(4)Department of Cell Biology and Chemical Physiology, Institute for Childhood
and Neglected Diseases, The Scripps Research Institute, La Jolla, CA, USA
(5)Proteostasis Therapeutics Inc., Cambridge, MA, USA
(6)Department of Chemistry, The Scripps Research Institute, Scripps Florida
(7)Discovery Biology, Drug Metabolism and Pharmacokinetics, The Scripps Research
Institute Florida
Protein homeostasis, also called proteostasis, is critical for cellular health
and its dysregulation is implicated in aging, cancer, metabolic disease, and
neurodegenerative disorders. Proteostasis involves compartmentalized cellular
responses (e.g. Heat Shock Response in the cytoplasm, Unfolded Protein Response
in the mitochondria and endoplasmic reticulum) that limit protein misfolding and
aggregation. Diseases of protein conformation are characterized by inefficient
induction of these responses. As a result, identification of molecules that
activate cellular stress responses and increase proteostasis may be useful for
maintaining cell health. Here, we report on high throughput screening efforts
that resulted in identification of a novel activator of heat shock protein 70
(Hsp70): ML346. Probe ML346 belongs to the barbituric acid scaffold. ML346
induces HSF-1-dependent chaperone expression and restores protein folding in
conformational disease models. These effects are mediated by novel mechanisms
involving FOXO, HSF-1, and Nfr-2.
PMID: 23833797 |
http://www.ncbi.nlm.nih.gov/pubmed/23784008 | 1. Eur J Clin Pharmacol. 2013 Nov;69(11):1875-81. doi: 10.1007/s00228-013-1550-4.
Epub 2013 Jun 20.
Evaluation of coagulation assays versus LC-MS/MS for determinations of
dabigatran concentrations in plasma.
Antovic JP(1), Skeppholm M, Eintrei J, Boija EE, Söderblom L, Norberg EM, Onelöv
L, Rönquist-Nii Y, Pohanka A, Beck O, Hjemdahl P, Malmström RE.
Author information:
(1)Department of Coagulation Research, Institute for Molecular Medicine and
Surgery, Karolinska Institutet, & Department of Clinical Chemistry, Karolinska
University Hospital, Stockholm, Sweden, [email protected].
BACKGROUND: Dabigatran is an oral direct thrombin inhibitor for which routine
laboratory monitoring is currently not recommended. However, there are
situations in which measurements of the drug and its effect are desirable. We
therefore compared and validated different coagulation methods for assessments
of dabigatran in clinical samples in relation to measurements of plasma
dabigatran, without the purpose of establishing effective and safe
concentrations of dabigatran in plasma.
METHODS: Samples were obtained from 70 atrial fibrillation patients treated with
dabigatran etexilate. Plasma concentrations were measured using liquid
chromatography-tandem mass spectrometry (LC-MS/MS) and were compared with
coagulation methods Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay
(ECA), as well as with prothrombin time-international normalized ratio (PT-INR)
and activated partial thromboplastin time (aPTT).
RESULTS: A wide range of dabigatran concentrations was determined by LC-MS/MS
(<0.5-586 ng/mL). Correlations between LC-MS/MS results and estimated
concentrations were excellent for both HTI and ECA overall (r(2) = 0.97 and 0.96
respectively, p < 0.0001), but the precision and variability of these assays
were not fully satisfactory in the low range of dabigatran plasma
concentrations, in which ECA performed better than HTI. aPTT performed poorly,
and was normal (<40 s) even with dabigatran levels of 60 ng/mL. PT-INR was
normal even at supratherapeutic dabigatran concentrations.
CONCLUSION: LC-MS/MS is the gold standard for measurements of dabigatran in
plasma. Alternatively, either HTI or ECA assays may be used, but neither of
these assays is dependable when monitoring low levels or to infer total absence
of dabigatran. The aPTT assay is relatively insensitive to dabigatran, and
normal aPTT results may be observed even with therapeutic dabigatran
concentrations.
DOI: 10.1007/s00228-013-1550-4
PMID: 23784008 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23140179 | 1. J Biomol Struct Dyn. 2013;31(11):1324-36. doi: 10.1080/07391102.2012.736757.
Epub 2012 Nov 12.
Compensatory nature of Chargaff's second parity rule.
Rapoport AE(1), Trifonov EN.
Author information:
(1)a Genome Diversity Center, Institute of Evolution, University of Haifa ,
Mount Carmel, Haifa , 31905 , Israel .
The second parity rule of Chargaff (A≈T and G≈C within one strand) holds all
over the living world with minor exceptions. It is maintained with higher
accuracy for long sequences. The question addressed in the article is how
different sequence types, with different biases from the parity, contribute to
the general effect. It appears that the sequence segments with biases of
opposite sign are intermingled, so that with sufficient sequence lengths the
parity is established. The parity rule seems to be a cumulative result of a
number of independent processes in the genome evolution, with the parity as
their intrinsic property. Symmetrical appearance of simple repeats and of Alu
sequences in the human DNA strands, and other contributions to the Chargaff
parity II rule are discussed.
DOI: 10.1080/07391102.2012.736757
PMID: 23140179 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23664865 | 1. N Biotechnol. 2013 Jun 25;30(5):461-74. doi: 10.1016/j.nbt.2013.04.007. Epub
2013 May 7.
Channelrhodopsins: visual regeneration and neural activation by a light switch.
G N(1), Tan A, Farhatnia Y, Rajadas J, Hamblin MR, Khaw PT, Seifalian AM.
Author information:
(1)Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery &
Interventional Science, University College London, London, UK.
The advent of optogenetics provides a new direction for the field of
neuroscience and biotechnology, serving both as a refined investigative tool and
as potential cure for many medical conditions via genetic manipulation. Although
still in its infancy, recent advances in optogenetics has made it possible to
remotely manipulate in vivo cellular functions using light. Coined Nature
Methods' 'Method of the Year' in 2010, the optogenetic toolbox has the potential
to control cell, tissue and even animal behaviour. This optogenetic toolbox
consists of light-sensitive proteins that are able to modulate membrane
potential in response to light. Channelrhodopsins (ChR) are light-gated
microbial ion channels, which were first described in green algae. ChR2 (a
subset of ChR) is a seven transmembrane α helix protein, which evokes membrane
depolarization and mediates an action potential upon photostimulation with blue
(470 nm) light. By contrast to other seven-transmembrane proteins that require
second messengers to open ion channels, ChR2 form ion channels themselves,
allowing ultrafast depolarization (within 50 milliseconds of illumination). It
has been shown that integration of ChR2 into various tissues of mice can
activate neural circuits, control heart muscle contractions, and even restore
breathing after spinal cord injury. More compellingly, a plethora of evidence
has indicated that artificial expression of ChR2 in retinal ganglion cells can
reinstate visual perception in mice with retinal degeneration.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nbt.2013.04.007
PMCID: PMC3713181
PMID: 23664865 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22647359 | 1. Cancer J. 2012 May-Jun;18(3):232-7. doi: 10.1097/PPO.0b013e318258b75b.
The duality of oncomiR addiction in the maintenance and treatment of cancer.
Cheng CJ(1), Slack FJ.
Author information:
(1)Department of Molecular Biophysics and Biochemistry, Yale University, New
Haven, CT 06520, USA.
It has long been established that cancers can become addicted to particular
oncogenes. Despite the genetic complexity that governs tumorigenesis, certain
cancers can exhibit a critical dependency on the expression of a single
oncogene, which when removed leads to death of the cancer cell. Recent
observations on the relationships between regulatory RNAs and cancer have
revealed that this concept of oncogene addiction extends to microRNAs (miRNAs)
as well. Certain cancers exhibit a dependency on the expression of a single
oncogenic miRNA, or oncomiR. The field of miRNA biology and its involvement in
diseases such as cancer have seen tremendous advances over the past decade.
However, little is known about the phenomenon of oncomiR addiction. In this
review, we introduce the concept of proto-oncomiRs, or miRNAs that gain
oncogenic activity after an initiating event. Furthermore, by highlighting the
role of proto-oncomiRs in generating malignant phenotypes, we glean possible
insights into the mechanisms that guide oncomiR addiction. In addition, toward
the realization of genetically driven personalized medicine, some of the most
clinically successful anticancer strategies have involved targeting addictive
oncogenes such as HER2, BCR/ABL, EGFR, and VEGF. Elucidating how addictive
miRNAs can perpetuate cancer may reveal additional critical molecular targets to
exploit for therapeutic purposes. Therefore, in this review, we also summarize
the field of anti-miRNA therapeutics, in which antisense and nanoscale delivery
technologies are the driving force. Addictive oncomiRs are a double-edged sword;
addicted cancers are dependent on oncomiRs that are highly potent therapeutic
targets. Dissection of this phenomenon may reveal the mechanisms through which
lynchpin miRNAs can perpetuate cancer and present a new paradigm for miRNA-based
cancer therapy.
DOI: 10.1097/PPO.0b013e318258b75b
PMCID: PMC3369429
PMID: 22647359 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24092929 | 1. J Am Soc Nephrol. 2013 Nov;24(11):1769-81. doi: 10.1681/ASN.2012111080. Epub
2013 Oct 3.
Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced
tubulointerstitial lesions.
Yamahara K(1), Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M, Araki H,
Isshiki K, Araki S, Haneda M, Matsusaka T, Kashiwagi A, Maegawa H, Uzu T.
Author information:
(1)Department of Medicine, Shiga University of Medical Science, Otsu, Shiga,
Japan;
Comment in
J Am Soc Nephrol. 2013 Nov;24(11):1711-3. doi: 10.1681/ASN.2013070794.
Obesity is an independent risk factor for renal dysfunction in patients with
CKDs, including diabetic nephropathy, but the mechanism underlying this
connection remains unclear. Autophagy is an intracellular degradation system
that maintains intracellular homeostasis by removing damaged proteins and
organelles, and autophagy insufficiency is associated with the pathogenesis of
obesity-related diseases. We therefore examined the role of autophagy in
obesity-mediated exacerbation of proteinuria-induced proximal tubular epithelial
cell damage in mice and in human renal biopsy specimens. In nonobese mice, overt
proteinuria, induced by intraperitoneal free fatty acid-albumin overload, led to
mild tubular damage and apoptosis, and activated autophagy in proximal tubules
reabsorbing urinary albumin. In contrast, diet-induced obesity suppressed
proteinuria-induced autophagy and exacerbated proteinuria-induced tubular cell
damage. Proximal tubule-specific autophagy-deficient mice, resulting from an
Atg5 gene deletion, subjected to intraperitoneal free fatty acid-albumin
overload developed severe proteinuria-induced tubular damage, suggesting that
proteinuria-induced autophagy is renoprotective. Mammalian target of rapamycin
(mTOR), a potent suppressor of autophagy, was activated in proximal tubules of
obese mice, and treatment with an mTOR inhibitor ameliorated obesity-mediated
autophagy insufficiency. Furthermore, both mTOR hyperactivation and autophagy
suppression were observed in tubular cells of specimens obtained from obese
patients with proteinuria. Thus, in addition to enhancing the understanding of
obesity-related cell vulnerability in the kidneys, these results suggest that
restoring the renoprotective action of autophagy in proximal tubules may improve
renal outcomes in obese patients.
DOI: 10.1681/ASN.2012111080
PMCID: PMC3810079
PMID: 24092929 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15665295 | 1. Cancer Res. 2005 Jan 1;65(1):195-202.
Implication of STAT3 signaling in human colonic cancer cells during intestinal
trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated
cellular invasion and tumor growth.
Rivat C(1), Rodrigues S, Bruyneel E, Piétu G, Robert A, Redeuilh G, Bracke M,
Gespach C, Attoub S.
Author information:
(1)Institut National de la Sante et de la Recherche Medicale U482, Hôpital
Saint-Antoine, Paris, France. [email protected]
Erratum in
Cancer Res. 2005 Mar 15;65(6):2505. Christine, Rivat [corrected to Rivat,
Christine]; Sylvie, Rodrigues [corrected to Rodrigues, Sylvie]; Erik, Bruyneel
[corrected to Bruyneel, Erik]; Geneviéve, Piétu [corrected to Piétu, Geneviéve];
Amélie, Robert [corrected to Robert, Amélie]; Gérar.
Signal transducer and activator of transcription (STAT) 3 is overexpressed or
activated in most types of human tumors and has been classified as an oncogene.
In the present study, we investigated the contribution of the STAT3s to the
proinvasive activity of trefoil factors (TFF) and vascular endothelial growth
factor (VEGF) in human colorectal cancer cells HCT8/S11 expressing VEGF
receptors. Both intestinal trefoil peptide (TFF3) and VEGF, but not pS2 (TFF1),
activate STAT3 signaling through Tyr(705) phosphorylation of both STAT3alpha and
STAT3beta isoforms. Blockade of STAT3 signaling by STAT3beta, depletion of the
STAT3alpha/beta isoforms by RNA interference, and pharmacologic inhibition of
STAT3alpha/beta phosphorylation by cucurbitacin or STAT3 inhibitory peptide
abrogates TFF- and VEGF-induced cellular invasion and reduces the growth of
HCT8/S11 tumor xenografts in athymic mice. Differential gene expression analysis
using DNA microarrays revealed that overexpression of STAT3beta down-regulates
the VEGF receptors Flt-1, neuropilins 1 and 2, and the inhibitor of DNA
binding/differentiation (Id-2) gene product involved in the neoplastic
transformation. Taken together, our data suggest that TFF3 and the essential
tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through
STAT3 signaling in human colorectal cancer cells. We also validate new
therapeutic strategies targeting STAT3 signaling by pharmacologic inhibitors and
RNA interference for the treatment of colorectal cancer patients.
PMID: 15665295 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17559560 | 1. BJU Int. 2007 Sep;100(3):533-5. doi: 10.1111/j.1464-410X.2007.07037.x. Epub
2007 Jun 8.
Progression after docetaxel-based chemotherapy in androgen-independent prostate
cancer.
Sella A(1), Sternberg C, Kovel S, Yarom N, Skoneczna I.
Author information:
(1)Department of Oncology, Assaf Harofeh Medical Center, Zerifin (affiliated to
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv), Israel.
[email protected]
OBJECTIVE: To assess the clinical pattern of progression and prostate-specific
antigen doubling time (PSA-DT) after exposure to docetaxel-based chemotherapy in
patients with androgen-independent prostate cancer (AIPC).
PATIENTS AND METHODS: Fifty-five patients received docetaxel-based chemotherapy;
data were collected retrospectively from three different departments.
Progression was known in 44 (79%) and the PSA-DT was available in 33 patients.
RESULTS: Of the 29 patients with soft-tissue and soft-tissue plus bone
metastases, 22 (76%) developed soft-tissue progression. Among the 35 patients
with bone and bone plus soft-tissue metastases, 27 (77%) had osseous
progression. There was no difference between the PSA-DT at progression before
and after docetaxel-based therapy (mean 3.1 vs 2.7 months, P = 0.592, Student's
t-test.). However, the median (range) PSA-DT at progression after
docetaxel-based therapy was 0.84 (0.3-4) months in patients with a PSA response,
significantly shorter than the median of 3.1 (0.3-12) months of patients with no
biochemical response (P = 0.002, Student's t-test). The PSA-DT dynamics at
progression had no effect on survival (P = 0.63, log-rank test).
CONCLUSION: The pattern of progression after docetaxel-based chemotherapy is
predominantly osseous in patient with bone metastases and mostly soft-tissue in
those with soft-tissue disease. Progression after docetaxel-based chemotherapy
in AIPC does not modify the PSA-DT before docetaxel. Evaluation of a larger
population is needed to assess the clinical relevance of PSA dynamics after
docetaxel therapy.
DOI: 10.1111/j.1464-410X.2007.07037.x
PMID: 17559560 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11583357 | 1. Int Urol Nephrol. 2001;32(3):381-8. doi: 10.1023/a:1017569621165.
Pilot study of the practical relevance of a one-step test for prostate-specific
antigen in capillary blood to improve the acceptance rate in the early detection
program of prostate carcinoma.
Berg W(1), Linder C, Eschholz G, Schubert J.
Author information:
(1)Department of Urology, University Hospital, Friedrich-Schiller-University
Jena, Germany. [email protected]
OBJECTIVE: Current studies have proven that early, organ-confined stages of
prostate cancer can be diagnosed through screening based on PSA levels, thus
reducing cancer mortality. Here we report about our experience using an
innovative one-step test for PSA in capillary blood.
METHODS: The incubation time for a 50 microl blood sample with the indicator
strip is 12 minutes until the qualitative visual results (<4.0 ng/ml or > or = 4
ng/ml) appear. In cooperation with urologists and accompanied by an extensive
information campaign, the one-step test was made available free of charge to all
men between the ages of 45 and 75 in all 28 pharmacies of our city (100,000
inhabitants).
RESULTS: The test's acceptance rate among the 2,119 participants between the
ages of 45 and 75 years amounted to 13.0%. Fifteen percent of all the tests
conducted showed a positive PSA result (> or = 4 ng/ml). Prostate carcinoma was
histologically confirmed in 14 (0.66%) of the men, nine times in the early stage
(T2) and five times in the clinical stage (T3), corresponding to an incidence of
circa 650 cases per 100,000 men in the target age group.
CONCLUSIONS: This newly developed PSA test system can enhance the acceptance
rate and effectiveness of medical check-ups for prostate cancer, because it is
easy-to-use, cost-effective and accurate (specificity 81.3%, sensitivity 91.1%).
The test should be always conducted by an experienced physician or pharmacist.
It is not a substitute for a regular physical examination (DRE, TRUS,
biopsy...).
DOI: 10.1023/a:1017569621165
PMID: 11583357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21209239 | 1. J Clin Pharmacol. 2011 Sep;51(9):1310-8. doi: 10.1177/0091270010381496. Epub
2011 Jan 5.
Fostamatinib, a Syk-kinase inhibitor, does not affect methotrexate
pharmacokinetics in patients with rheumatoid arthritis.
Baluom M(1), Samara E, Grossbard EB, Lau DT.
Author information:
(1)Rigel Pharmaceuticals, Inc, 1180 Veterans Blvd., South San Francisco, CA
94080, USA.
Fostamatinib (R788) is being investigated as an add-on therapy for the treatment
of rheumatoid arthritis (RA) in patients with inadequate response to
methotrexate (MTX). This study evaluated the potential pharmacokinetic
interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX
regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received
100 mg of R788 orally, and 4 subjects received a matching placebo twice daily
from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on
days 1 and 8 for MTX and 7-hydroxymethotrexate (7-OH-MTX), and days 3 and 9 for
R788 and its active metabolite, R406. MTX and 7-OH-MTX pharmacokinetic
parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to
day 1 ratios (90% confidence intervals) of maximum concentration and area under
the plasma concentration-time curve estimates were 1.01 (0.85-1.20) and 1.12
(0.90-1.40) for MTX and 1.06 (0.82-1.35) and 1.06 (0.83-1.36) for 7-OH-MTX,
respectively. Urinary excretion of MTX and 7-OH-MTX was also similar with or
without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively.
The data suggest that there is no clinically significant pharmacokinetic
interaction of R788 and MTX in RA patients.
DOI: 10.1177/0091270010381496
PMID: 21209239 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15925651 | 1. Med Clin North Am. 2005 Jul;89(4):805-16. doi: 10.1016/j.mcna.2005.02.003.
Minority issues in prostate disease.
French DB(1), Jones LA.
Author information:
(1)Department of Urology, University of Texas Health Science Center at San
Antonio, MC 7845, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
This article has discussed the increased incidence and disproportionately
increased mortality of prostate cancer among African American men.Although the
exact reasons are unknown, genetics may play a role, in addition to health care
practices. Morbidity from other disease states, such as diabetes, obesity, or
hypertension, may influence the overall survival of patients with prostate
cancer. Current research tools will continue to explore biologic differences
between the races; however, socioeconomic status and access to health care must
not be overlooked. Several studies have demonstrated that similar disease stages
and equal access to health care will result in similar outcomes. It is
recognized that screening for prostate cancer will remain a controversial topic.
Several influential professional societies recommend against screening and other
professional societies endorse screening. Large-scale trials are currently
underway hoping to answer this critical question. Since the advent of current
screening tools, however, it seems that the overall mortality for prostate
cancer has decreased and this cannot be ignored. Certainly, screening programs
and clinical trials have traditionally had difficulty in recruiting minority
participants, although more recent trials seem to be finding success. A primary
care physician who is viewed as competent by their patients can certainly have a
positive impact on their African American patients' willingness to participate
in studies and screening programs. Most importantly, on the individual level,
primary care physicians can provide a great service to their minority patients
by offering educational materials on prostate cancer and by offering screening
to qualified patients. The current American Urologic Association and National
Cancer Institute guidelines recommend offering screening to all men age 50 and
above. African American men or men with a first-degree relative with prostate
cancer should be offered screening beginning at age 40. Proper screening
consists of both a digital rectal examination to assess for asymmetry or nodules
of the prostate and a serum PSA. Current recommendations are that individuals
with a serum PSA greater than 4 ng/mL ora prostate nodule or asymmetric prostate
should be referred to an urologist,where a biopsy can be performed easily in the
office setting.The PSA cutoff of 4 has recently been questioned. A study by
Thompson et al [31] evaluated 2950 men with a PSA of 4 or less with prostate
biopsy.They found that the risk of prostate cancer in men with a PSA between 3.1
and 4 was 26.9% and that 25% of these men with prostate cancer had high-grade
disease. All men found to have cancer had T1 disease. The clinical relevance of
this surprisingly high rate of prostate cancer in men with a normal PSA is yet
to be determined and is pending in studies on the ultimate effect of screening
on mortality from prostate cancer. This information is not intended to confuse
the issue, but intended to provide the most up-to-date information and allow for
the best clinical decision making by the primary care physician. What can
currently be recommended is if a patient is concerned about his possibility of
having prostate cancer despite a normal PSA, a referral to an urologist to at
least further discuss the issue may be in order. This may be especially true if
the patient is African American or has a family history of prostate cancer at an
early age.
DOI: 10.1016/j.mcna.2005.02.003
PMID: 15925651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16869776 | 1. Cold Spring Harb Symp Quant Biol. 2005;70:389-97. doi:
10.1101/sqb.2005.70.042.
Is oncogene addiction angiogenesis-dependent?
Folkman J(1), Ryeom S.
Author information:
(1)The Vascular Biology Program, Department of Surgery, Children's Hospital and
Harvard Medical School, Boston, Massachusetts 02115, USA.
Does an activated oncogene that initiates tumor growth need to remain activated
to maintain the cancer phenotype? This question has been answered affirmatively
by experiments in which doxycycline-regulated oncogene activation induces growth
of large tumors that regress completely upon oncogene inactivation--a phenomenon
called oncogene addiction. We assemble here the evidence that oncogene addiction
is angiogenesis-dependent. Although activated oncogenes increase tumor cell
proliferation and decrease their apoptosis, these activities are not sufficient
to expand tumor mass beyond a microscopic size. Oncogenes must also induce tumor
angiogenesis for expansion of tumor mass. We propose experiments to validate the
"endothelial centric" hypothesis of oncogene addiction.
DOI: 10.1101/sqb.2005.70.042
PMID: 16869776 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23748382 | 1. Psychopharmacology (Berl). 2013 Dec;230(3):345-52. doi:
10.1007/s00213-013-3158-x. Epub 2013 Jun 10.
Effects of the adenosine A2A antagonist istradefylline on cognitive performance
in rats with a 6-OHDA lesion in prefrontal cortex.
Kadowaki Horita T(1), Kobayashi M, Mori A, Jenner P, Kanda T.
Author information:
(1)Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin
Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
RATIONALE: Altered cognitive function is a common feature of both the early and
later stages of Parkinson's disease (PD) that involves alterations in cortical
dopamine content. Adenosine A2A antagonists, such as istradefylline, improve
motor function in PD, but their effect on cognitive impairment has not been
determined.
OBJECTIVE: The present study investigated whether impairment of working memory
due to the loss of dopaminergic input into the prefrontal cortex (PFC) is
reversed by administration of istradefylline. We also evaluated whether A2A
antagonist administration modulates dopamine levels in the PFC.
METHODS: Bilateral lesions of the dopaminergic input to the PFC were produced in
rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using
an object recognition task and delayed alternation task. The effects of
istradefylline, donepezil and methamphetamine on cognitive performance were
examined. In addition, the effect of istradefylline on extracellular dopamine
levels in the PFC was studied.
RESULTS: PFC dopamine levels and cognitive performance were significantly
reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine
improved cognitive performance of PFC-lesioned rats. Istradefylline increased
dopamine levels in the PFC in both normal and PFC-lesioned rats.
CONCLUSIONS: PFC dopaminergic input plays an important role in working memory
performance. Blockade of A2A receptors using istradefylline reverses the changes
in cognitive function, and this may be due to an increase in PFC dopamine
content. Adenosine A2A receptor antagonists not only improve motor performance
in PD but may also lead to improved cognition.
DOI: 10.1007/s00213-013-3158-x
PMID: 23748382 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19423177 | 1. Int J Cardiol. 2010 Oct 8;144(2):187-90. doi: 10.1016/j.ijcard.2009.03.137.
Epub 2009 May 7.
The relationship and prognostic impact of low-T3 syndrome and NT-pro-BNP in
cardiovascular patients.
Pfister R(1), Strack N, Wielckens K, Malchau G, Erdmann E, Schneider CA.
Author information:
(1)Department III of Internal Medicine, Herzzentrum, University of Cologne,
Kerpenerstr. 62, 50937 Cologne, Germany. [email protected]
OBJECTIVES: Low-T3 syndrome is highly prevalent and independently prognostic in
cardiovascular patients. The relationship and prognostic impact with the cardiac
marker NT-pro-BNP have not been thoroughly investigated.
METHODS: Thyroid hormone levels and NT-pro-BNP were assessed in 615 consecutive
patients hospitalized for cardiovascular disease. Patients with primary overt or
latent thyroid disorder, hormone replacement, thyreostatic and amiodarone
therapy were excluded. The association with and predictive impact on mortality
were examined.
RESULTS: 36 (7.1%) patients had low-T3 syndrome. After adjustment for known
confounders, NT-pro-BNP was significantly associated with fT3 and low-T3
syndrome. fT3 (HR 0.58, 95%CI 0.34-0.98) and low-T3 syndrome (HR 3.0, 95%CI
1.4-6.3) were predictive for mortality after adjustment for NT-pro-BNP levels
and other cardiovascular prognostic variables. In patients with fT3 levels
within the normal range, fT3 and NT-pro-BNP stratified by median values showed
complementary prognostic information with the highest risk for mortality in
patients with low normal fT3 and high NT-pro-BNP (HR 10.5, 95%CI 3.2-34.6).
CONCLUSIONS: fT3 and low-T3 syndrome are significantly related to NT-pro-BNP in
patients with cardiovascular disease, but are predictors of mortality
independently of NT-pro-BNP and other known cardiovascular risk parameters.
Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ijcard.2009.03.137
PMID: 19423177 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16867087 | 1. Anaesthesia. 2006 Aug;61(8):752-7. doi: 10.1111/j.1365-2044.2006.04715.x.
Propofol/remifentanil vs sevoflurane/remifentanil for long lasting surgical
procedures: a randomised controlled trial.
Höcker J(1), Tonner PH, Böllert P, Paris A, Scholz J, Meier-Paika C, Bein B.
Author information:
(1)Department of Anaesthesiology and Intensive Care Medicine, University
Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 21, D-24105, Kiel,
Germany.
We compared the haemodynamics, emergence and recovery characteristics of total
intravenous anaesthesia using propofol/remifentanil with
sevoflurane/remifentanil anaesthesia, under bispectral index guidance, in 103
patients undergoing surgical procedures lasting > 3.5 h. Time to tracheal
extubation was significantly shorter in the propofol group than in the
sevoflurane group (mean (SD) 8.3 (3.5) min vs 10.8 (4.6) min, respectively; p =
0.0024), but further recovery was comparable in both groups. There were no
significant differences in haemodynamic parameters, intensity of pain or
postoperative nausea and vomiting. During and after anaesthesia of comparable
depth for long lasting surgical procedures, both propofol/remifentanil and
sevoflurane/remifentanil enable haemodynamic stability and fast emergence. The
shorter time to extubation in the propofol group does not offer a relevant
clinical advantage.
DOI: 10.1111/j.1365-2044.2006.04715.x
PMID: 16867087 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25060859 | 1. Sci Rep. 2014 Jul 25;4:5838. doi: 10.1038/srep05838.
Channelrhodopsin2 current during the action potential: "optical AP clamp" and
approximation.
Entcheva E(1), Williams JC(1).
Author information:
(1)Department of Biomedical Engineering, Stony Brook University, Stony Brook,
USA.
The most widely used optogenetic tool, Channelrhodopsin2 (ChR2), is both light-
and voltage-sensitive. A light-triggered action potential or light-driven
perturbations of ongoing electrical activity provide instant voltage feedback,
shaping ChR2 current. Therefore, depending on the cell type and the light pulse
duration, the typically reported voltage-clamp-measured ChR2 current traces are
often not a good surrogate for the ChR2 current during optically-triggered
action potentials. We discuss two experimental methods to reveal ChR2 current
during an action potential: an "optical AP clamp" and its approximation
employing measured current-voltage curve for ChR2. The methods are applicable to
voltage- and light-sensitive ion currents operating in excitable cells, e.g.
cardiomyocytes or neurons.
DOI: 10.1038/srep05838
PMCID: PMC4894422
PMID: 25060859 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17958891 | 1. Orphanet J Rare Dis. 2007 Oct 24;2:42. doi: 10.1186/1750-1172-2-42.
Mowat-Wilson syndrome.
Garavelli L(1), Mainardi PC.
Author information:
(1)Clinical Genetics Unit, Obstetric and Pediatric Department, S, Maria Nuova
Hospital, Reggio Emilia, Italy. [email protected]
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome
characterized by a distinct facial phenotype (high forehead, frontal bossing,
large eyebrows, medially flaring and sparse in the middle part, hypertelorism,
deep set but large eyes, large and uplifted ear lobes, with a central
depression, saddle nose with prominent rounded nasal tip, prominent columella,
open mouth, with M-shaped upper lip, frequent smiling, and a prominent but
narrow and triangular pointed chin), moderate-to-severe intellectual deficiency,
epilepsy and variable congenital malformations including Hirschsprung disease
(HSCR), genitourinary anomalies (in particular hypospadias in males), congenital
heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence
of MWS is currently unknown, but 171 patients have been reported so far. It
seems probable that MWS is under-diagnosed, particularly in patients without
HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger
E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date,
over 100 deletions/mutations have been reported in patients with a typical
phenotype; they are frequently whole gene deletions or truncating mutations,
suggesting that haploinsufficiency is the main pathological mechanism. Studies
of genotype-phenotype analysis show that facial gestalt and delayed psychomotor
development are constant clinical features, while the frequent and severe
congenital malformations are variable. In a small number of patients, unusual
mutations can lead to an atypical phenotype. The facial phenotype is
particularly important for the initial clinical diagnosis and provides the
hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The
majority of MWS cases reported so far were sporadic, therefore the recurrence
risk is low. Nevertheless, rare cases of sibling recurrence have been observed.
Congenital malformations and seizures require precocious clinical investigation
with intervention of several specialists (including neonatologists and
pediatricians). Psychomotor development is delayed in all patients, therefore
rehabilitation (physical therapy, psychomotor and speech therapy) should be
started as soon as possible.
DOI: 10.1186/1750-1172-2-42
PMCID: PMC2174447
PMID: 17958891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16449486 | 1. Am J Psychiatry. 2006 Feb;163(2):303-12. doi: 10.1176/appi.ajp.163.2.303.
Multicenter investigation of the opioid antagonist nalmefene in the treatment of
pathological gambling.
Grant JE(1), Potenza MN, Hollander E, Cunningham-Williams R, Nurminen T, Smits
G, Kallio A.
Author information:
(1)Department of Psychiatry, University of Minnesota Medical School, 2450
Riverside Avenue, Minneapolis, MN 55454, USA. [email protected]
Comment in
Am J Psychiatry. 2006 Feb;163(2):180-1. doi: 10.1176/appi.ajp.163.2.180.
OBJECTIVE: Pathological gambling is a disabling disorder experienced by
approximately 1%-2% of adults and for which there are few empirically validated
treatments. The authors examined the efficacy and tolerability of the opioid
antagonist nalmefene in the treatment of adults with pathological gambling.
METHOD: A 16-week, randomized, dose-ranging, double-blind, placebo-controlled
trial was conducted at 15 outpatient treatment centers across the United States
between March 2002 and April 2003. Two hundred seven persons with DSM-IV
pathological gambling were randomly assigned to receive nalmefene (25 mg/day, 50
mg/day, or 100 mg/day) or placebo. Scores on the primary outcome measure
(Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling) were
analyzed by using a linear mixed-effects model.
RESULTS: Estimated regression coefficients showed that the 25 mg/day and 50
mg/day nalmefene groups had significantly different scores on the Yale-Brown
Obsessive Compulsive Scale Modified for Pathological Gambling, compared to the
placebo group. A total of 59.2% of the subjects who received 25 mg/day of
nalmefene were rated as "much improved" or "very much improved" at the last
evaluation, compared to 34.0% of those who received placebo. Adverse experiences
included nausea, dizziness, and insomnia.
CONCLUSIONS: Subjects who received nalmefene had a statistically significant
reduction in severity of pathological gambling. Low-dose nalmefene (25 mg/day)
appeared efficacious and was associated with few adverse events. Higher doses
(50 mg/day and 100 mg/day) resulted in intolerable side effects.
DOI: 10.1176/appi.ajp.163.2.303
PMID: 16449486 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23390130 | 1. Hum Mol Genet. 2013 May 1;22(9):1856-66. doi: 10.1093/hmg/ddt038. Epub 2013
Feb 5.
Site-specific Mtm1 mutagenesis by an AAV-Cre vector reveals that myotubularin is
essential in adult muscle.
Joubert R(1), Vignaud A, Le M, Moal C, Messaddeq N, Buj-Bello A.
Author information:
(1)Department of Research and Development, Généthon, INSERM, Evry, France
Manipulation of the mouse genome by site-specific mutagenesis has been
extensively used to study gene function and model human disorders. Mouse models
of myotubular myopathy (XLMTM), a severe congenital muscular disorder due to
loss-of-function mutations in the MTM1 gene, have been generated by homologous
recombination and shown that myotubularin is essential for skeletal muscle.
However, since the Mtm1 deletion occurred constitutively or shortly after birth
in these mice, it is not known whether myotubularin is required during
adulthood, an important issue in the context of not only muscle biology but also
therapies. To delete the Mtm1 gene in adult muscle fibers, we constructed a
recombinant adeno-associated vector (AAV) that expresses the Cre recombinase
under the muscle-specific desmin promoter. We report that a single injection of
this vector into muscles of 3-month-old Mtm1 conditional mice leads to a
myotubular myopathy phenotype with myofiber atrophy, disorganization of
organelle positioning, such as mitochondria and nuclei, T-tubule defects and
severe muscle weakness. In addition, our results show that MTM1-related atrophy
and dysfunction correlate with abnormalities in satellite cell number and
markers of autophagy, protein synthesis and neuromuscular junction transmission.
The expression level of atrogenes was also analyzed. Therefore, we provide a
valuable tissue model that recapitulates the main features of the disease, and
it is useful to study pathogenesis and evaluate therapeutic strategies. We
establish the proof-of-concept that myotubularin is required for the proper
function of skeletal muscle during adulthood, suggesting that therapies will be
required for the entire life of XLMTM patients.
DOI: 10.1093/hmg/ddt038
PMID: 23390130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23652451 | 1. Contrib Nephrol. 2013;179:81-91. doi: 10.1159/000346726. Epub 2013 May 3.
Preventing stroke and systemic embolism in renal patients with atrial
fibrillation: focus on anticoagulation.
Ahmad Y(1), Lip GY.
Author information:
(1)University of Birmingham Centre for Cardiovascular Sciences, City Hospital,
Birmingham, UK.
Chronic kidney disease and atrial fibrillation (AF) commonly coexist, and data
suggest that renal patients have AF rates in excess of double that encountered
in the general population. These patients are at increased risk of stroke,
regardless of the presence or absence of AF. Furthermore, a lower GFR causes
increased thromboembolic risk in patients with AF - independent of other risk
factors. The dilemma facing clinicians treating this cohort of patients is that
renal insufficiency confers both a thromboembolic and a bleeding risk. Renal
disease also commonly coexists with other risk factors for stroke and bleeding
such as hypertension and advanced age. Furthermore, bleeding risk tracks stroke
risk and many risk factors are common to both thromboembolism and haemorrhage.
Patients with severe renal impairment are also actively excluded from the
majority of trials for stroke prevention in AF, including those trials which
informed the development of stroke risk factor scoring schemes. Therefore,
patients with renal disease and AF present a unique management challenge. The
available data suggests that the benefit from warfarin in terms of stroke
reduction is not as clear as in the general population, and there is an
increased risk of bleeding complications and even ectopic vascular
calcification. Thus, it is problematic to extrapolate the benefits of warfarin
in the general population to a subgroup that has been actively excluded from
clinical trials. The new oral anticoagulants have relatively little data in
patients with severe renal impairment, and all have an element of renal
excretion. There is a need for large randomised control trials in patients with
renal insufficiency and on haemodialysis to provide a bank of high-quality
scientific data on which clinicians can base their management decisions. Until
then, we must adopt a pragmatic approach which involves careful consideration of
the relative risk of stroke and bleeding in each individual patient.
Copyright © 2013 S. Karger AG, Basel.
DOI: 10.1159/000346726
PMID: 23652451 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10215407 | 1. Hum Mutat. 1998;11(4):331-2. doi:
10.1002/(SICI)1098-1004(1998)11:4<331::AID-HUMU12>3.0.CO;2-3.
Identification of a large insertion and two novel point mutations (3671del8 and
S1221X) in tuberous sclerosis complex (TSC) patients. Mutations in brief no.
119. Online.
Wang Q(1), Verhoef S, Tempelaars AM, Bakker PL, Vrtel R, Hesseling-Janssen AL,
Nellist M, Oranje AP, Stroink H, Lindhout D, Halley DJ, van den Ouweland AM.
Author information:
(1)MGC Department, Clinical Genetics, Erasmus University, Rotterdam, The
Netherlands.
Important symptoms of tuberous sclerosis complex (TSC), an autosomal dominant
disorder, are hamartomata in several organs, mental retardation and epilepsy.
Either one of two loci can be involved (TSC1 and TSC2), of which the TSC2 gene
has been cloned. To date, only 35 mutations in the TSC2 gene have been described
ranging from large deletions to point mutations. Southern blot analysis using
cDNA clones of the TSC2 gene was performed on a cohort of 160 unrelated TSC
patients and revealed a 10 kb insertion. The insertion was also present in DNA
of the affected father. Both patients showed renal angiomyolipoma, hypomelanotic
macules and epilepsy. SSCP analysis of exons 1,2,3,9,12,14,30a and 36 identified
two mutations in exon 30a: 3671del8 and S1221X. Symptoms of the sporadic patient
with the 3671del8 mutation are cortical tubers, subependymal nodules, facial
angiofibroma, ungual fibroma, renal angiomyolipoma, hypomelanotic macules,
epilepsy and mental retardation. Clinical symptoms of the patient with the
S1221X mutation are facial angiofibroma, ungual fibroma, hypomelanotic macules,
epilepsy and mental retardation. His parents were negative for the S1221X
mutation, although a germline mosaicism can not be excluded. Besides the
previously described polymorphism 1596C->T, two rare variants were observed, a
substitution of C->T at position 1294 and at position 1299 C->A.
DOI: 10.1002/(SICI)1098-1004(1998)11:4<331::AID-HUMU12>3.0.CO;2-3
PMID: 10215407 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9657027 | 1. Ann Urol (Paris). 1998;32(3):128-32.
[Renal angiomyolipoma. Apropos of 11 cases].
[Article in French]
Benchekroun A(1), Lachkar A, Soumana A, Farih MH, Belahnech Z, Marzouk M, Faik
M.
Author information:
(1)Clinique Urologique A, CHU Ibn Sina, Rabat, Maroc.
The authors report their experience of 11 cases of renal angiomyolipoma over an
interval of 20 years, observed in 10 women (90.9%) and one man (9.1%) with a
mean age of 46 years (range: 21 to 63). Clinical symptoms were dominated by loin
pain (100%), haematuria (45.4%), lumbar mass (72.7%), fever (18%). In one woman,
AML was associated with "tuberous sclerosis". Preoperatively, the diagnosis was
established by ultrasound and CT scan in 45.4% of patients. The size of the
tumour varied from 7 to 14 cm in 10 patients and in one patient was only about
3.6 cm. Two women had bilateral tumours. Treatment consisted of total
nephrectomy in 7 patients, partial nephrectomy in 3 patients and tumourectomy in
one patient. The purpose of this study is to analyse the epidemiologic,
diagnostic and therapeutic aspects of this disease.
PMID: 9657027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21284609 | 1. Headache. 2011 Feb;51(2):272-86. doi: 10.1111/j.1526-4610.2010.01830.x.
Cluster headache--acute and prophylactic therapy.
Ashkenazi A(1), Schwedt T.
Author information:
(1)The Neurologic Group of Bucks/Montgomery County-Neurology, Doylestown, PA
18901, USA.
Cluster headache (CH) pain is the most severe of the primary headache syndromes.
It is characterized by periodic attacks of strictly unilateral pain associated
with ipsilateral cranial autonomic symptoms. The majority of patients have
episodic CH, with cluster periods that typically occur in a circannual rhythm,
while 10% suffer from the chronic form, with no significant remissions between
cluster periods. Sumatriptan injection or oxygen inhalation is the first-line
therapy for acute CH attacks, with the majority of patients responding to either
treatment. The calcium channel blocker verapamil is the drug of choice for CH
prevention. Other drugs that may be used for this purpose include lithium
carbonate, topiramate, valproic acid, gabapentin, and baclofen. Transitional
prophylaxis, most commonly using corticosteroids, helps to control the attacks
at the beginning of a cluster period. Peripheral neural blockade is effective
for short-term pain control. Recently, the therapeutic options for refractory CH
patients have expanded with the emergence of both peripheral (mostly occipital
nerve) and central (hypothalamic) neurostimulation. With the emergence of these
novel treatments, the role of ablative surgery in CH has declined.
© 2011 American Headache Society.
DOI: 10.1111/j.1526-4610.2010.01830.x
PMID: 21284609 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20945983 | 1. Biomark Med. 2010 Oct;4(5):713-21. doi: 10.2217/bmm.10.96.
Autosomal recessive mutations in the development of Parkinson's disease.
Lopez G(1), Sidransky E.
Author information:
(1)Medical Genetics Branch, National Human Genome Research Institute, NIH,
Bethesda, MD 20892-3708, USA.
Although Parkinson's disease was long considered a nongenetic disorder, it is
now clear that there are multiple predisposing genes, and that the disorder can
exhibit either Mendelian or non-Mendelian modes of inheritance. The
identification of several of these genes has provided important insights into
the pathogenesis of this common complex disorder. This article presents an
overview of the genes associated with autosomal recessive Parkinson's disease,
including Parkin (PARK2), PINK1 (PARK6), DJ1 (PARK7) and ATP13A2 (PARK9).
Recently, it was recognized that mutations in the gene encoding
glucocerebrosidase, the enzyme deficient in Gaucher disease, are associated with
an increased incidence of parkinsonism. While Gaucher disease is an autosomal
recessive inherited disorder, patients with Parkinson's disease can be Gaucher
heterozygotes or homozygotes. Elucidating the basis for this association may
shed light on new disease mechanisms that contribute to the development of
parkinsonism.
DOI: 10.2217/bmm.10.96
PMID: 20945983 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25598831 | 1. Drugs Context. 2014 Dec 19;3:212264. doi: 10.7573/dic.212264. eCollection
2014.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors: a growing class of
antidiabetic agents.
Vivian EM(1).
Author information:
(1)School of Pharmacy, University of Wisconsin, Madison, WI, USA.
Although several treatment options are available to reduce hyperglycemia, only
about half of individuals with diagnosed diabetes mellitus (DM) achieve
recommended glycemic targets. New agents that reduce blood glucose
concentrations by novel mechanisms and have acceptable safety profiles are
needed to improve glycemic control and reduce the complications associated with
type 2 diabetes mellitus (T2DM). The renal sodium-glucose co-transporter 2
(SGLT2) is responsible for reabsorption of most of the glucose filtered by the
kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and
action of insulin by inhibiting renal reabsorption of glucose, thereby promoting
the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin,
and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the
United States, Europe, and other countries. Canagliflozin, dapagliflozin, and
empagliflozin increase renal excretion of glucose and improve glycemic
parameters in patients with T2DM when used as monotherapy or in combination with
other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated
with weight reduction, lowered blood pressure, and a low intrinsic propensity to
cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are
well tolerated. Cases of genital infections and, in some studies, urinary tract
infections have been more frequent in canagliflozin-, dapagliflozin-, and
empagliflozin-treated patients compared with those receiving placebo. Evidence
from clinical trials suggests that SGLT2 inhibitors are a promising new
treatment option for T2DM.
DOI: 10.7573/dic.212264
PMCID: PMC4295914
PMID: 25598831 |
http://www.ncbi.nlm.nih.gov/pubmed/21653695 | 1. J Biol Chem. 2011 Aug 12;286(32):28080-8. doi: 10.1074/jbc.M111.237859. Epub
2011 Jun 8.
Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link
between Parkinson and Gaucher diseases.
Yap TL(1), Gruschus JM, Velayati A, Westbroek W, Goldin E, Moaven N, Sidransky
E, Lee JC.
Author information:
(1)Laboratory of Molecular Biophysics, National Heart Lung and Blood Institute,
National Human Genome Research Institute, National Institutes of Health,
Bethesda, Maryland 20892, USA.
The presynaptic protein α-synuclein (α-syn), particularly in its amyloid form,
is widely recognized for its involvement in Parkinson disease (PD). Recent
genetic studies reveal that mutations in the gene GBA are the most widespread
genetic risk factor for parkinsonism identified to date. GBA encodes for
glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage
disorder, Gaucher disease (GD). In this work, we investigated the possibility of
a physical linkage between α-syn and GCase, examining both wild type and the
GD-related N370S mutant enzyme. Using fluorescence and nuclear magnetic
resonance spectroscopy, we determined that α-syn and GCase interact selectively
under lysosomal solution conditions (pH 5.5) and mapped the interaction site to
the α-syn C-terminal residues, 118-137. This α-syn-GCase complex does not form
at pH 7.4 and is stabilized by electrostatics, with dissociation constants
ranging from 1.2 to 22 μm in the presence of 25 to 100 mm NaCl. Intriguingly,
the N370S mutant form of GCase has a reduced affinity for α-syn, as does the
inhibitor conduritol-β-epoxide-bound enzyme. Immunoprecipitation and
immunofluorescence studies verified this interaction in human tissue and
neuronal cell culture, respectively. Although our data do not preclude
protein-protein interactions in other cellular milieux, we suggest that the
α-syn-GCase association is favored in the lysosome, and that this noncovalent
interaction provides the groundwork to explore molecular mechanisms linking PD
with mutant GBA alleles.
DOI: 10.1074/jbc.M111.237859
PMCID: PMC3151053
PMID: 21653695 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23855662 | 1. Protein Pept Lett. 2014;21(8):847-57. doi: 10.2174/09298665113209990063.
Biomedical hypothesis generation by text mining and gene prioritization.
Petric I, Ligeti B, Gyorffy B, Pongor S(1).
Author information:
(1)Centre for Systems and Information Technologies, University of Nova Gorica,
Vipavska 13, SI-5000 Nova Gorica, Slovenia. [email protected].
Text mining methods can facilitate the generation of biomedical hypotheses by
suggesting novel associations between diseases and genes. Previously, we
developed a rare-term model called RaJoLink (Petric et al, J. Biomed. Inform.
42(2): 219-227, 2009) in which hypotheses are formulated on the basis of terms
rarely associated with a target domain. Since many current medical hypotheses
are formulated in terms of molecular entities and molecular mechanisms, here we
extend the methodology to proteins and genes, using a standardized vocabulary as
well as a gene/protein network model. The proposed enhanced RaJoLink rare-term
model combines text mining and gene prioritization approaches. Its utility is
illustrated by finding known as well as potential gene-disease associations in
ovarian cancer using MEDLINE abstracts and the STRING database.
DOI: 10.2174/09298665113209990063
PMID: 23855662 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11807557 | 1. Nature. 2002 Jan 24;415(6870):442-7. doi: 10.1038/415442a.
A calcium sensor in the sodium channel modulates cardiac excitability.
Tan HL(1), Kupershmidt S, Zhang R, Stepanovic S, Roden DM, Wilde AA, Anderson
ME, Balser JR.
Author information:
(1)Department of Anesthesiology, Vanderbilt University School of Medicine,
Nashville 37232, Tennessee, USA.
Sodium channels are principal molecular determinants responsible for myocardial
conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a
fundamental role in the coupling of cardiac myocyte excitation and contraction,
yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel
function have yet to be identified. Here we show that calmodulin (CaM), a
ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of
the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding
interaction significantly enhances slow inactivation-a channel-gating process
linked to life-threatening idiopathic ventricular arrhythmias. Mutations
targeted to the IQ domain disrupted CaM binding and eliminated
Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM
were restored by intracellular application of a peptide modelled after the IQ
domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1
function in a manner characteristic of the Brugada arrhythmia syndrome, but at
the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a
clinically benign (arrhythmia free) phenotype.
DOI: 10.1038/415442a
PMID: 11807557 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23429588 | 1. J Cardiovasc Pharmacol. 2013 May;61(5):444-51. doi:
10.1097/FJC.0b013e3182893d90.
Lack of a pharmacokinetic interaction between treprostinil diolamine and
sildenafil in healthy adult volunteers.
Gotzkowsky SK(1), Kumar P, Mottola D, Laliberte K.
Author information:
(1)Product Development, United Therapeutics Corporation, Research Triangle Park,
NC 27709, USA.
Treprostinil, a stable prostacyclin analogue used in the treatment of pulmonary
arterial hypertension, is in development as a sustained release oral tablet,
treprostinil diolamine (United Therapeutics Corp, Research Triangle Park, NC).
As combination therapy yields additional benefit in pulmonary arterial
hypertension, treprostinil diolamine may be used with sildenafil, a
phosphodiesterase-5 inhibitor. This study was designed to evaluate the presence
of a pharmacokinetic drug interaction between treprostinil diolamine and
sildenafil. Treprostinil is primarily metabolized by cytochrome (CYP) P450 2C8
with minor contribution from CYP2C9. Sildenafil is metabolized by CYP3A4 with
minor contribution from CYP2C9. Eighteen healthy volunteers were randomized to
receive 4.5 days each of (1) treprostinil diolamine alone, (2) sildenafil alone,
and (3) combination treprostinil diolamine and sildenafil in an open-label,
3-period, 3-sequence crossover study. The geometric mean ratio (90% confidence
intervals) for combination/agent alone of steady state area under the
concentration-time curve and peak concentration (Cmax) were 0.972 (0.824-1.145)
and 1.030 (0.900, 1.1-9), respectively, for treprostinil diolamine and were
0.881 (0.804-0.966) and 0.910 (0.876-0.946), respectively, for sildenafil. The
results suggest lack of a metabolic interaction between treprostinil diolamine
and sildenafil, as geometric mean ratio 90% confidence intervals were within
0.8-1.25. Combination therapy was well tolerated but had slightly higher rates
of nausea, headache, and extremity pain than monotherapy.
DOI: 10.1097/FJC.0b013e3182893d90
PMID: 23429588 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23185389 | 1. PLoS One. 2012;7(11):e49634. doi: 10.1371/journal.pone.0049634. Epub 2012 Nov
19.
Interactogeneous: disease gene prioritization using heterogeneous networks and
full topology scores.
Gonçalves JP(1), Francisco AP, Moreau Y, Madeira SC.
Author information:
(1)Knowledge Discovery and Bioinformatics Group, INESC-ID, Lisbon, Portugal.
[email protected]
Disease gene prioritization aims to suggest potential implications of genes in
disease susceptibility. Often accomplished in a guilt-by-association scheme,
promising candidates are sorted according to their relatedness to known disease
genes. Network-based methods have been successfully exploiting this concept by
capturing the interaction of genes or proteins into a score. Nonetheless, most
current approaches yield at least some of the following limitations: (1)
networks comprise only curated physical interactions leading to poor genome
coverage and density, and bias toward a particular source; (2) scores focus on
adjacencies (direct links) or the most direct paths (shortest paths) within a
constrained neighborhood around the disease genes, ignoring potentially
informative indirect paths; (3) global clustering is widely applied to partition
the network in an unsupervised manner, attributing little importance to prior
knowledge; (4) confidence weights and their contribution to edge differentiation
and ranking reliability are often disregarded. We hypothesize that network-based
prioritization related to local clustering on graphs and considering full
topology of weighted gene association networks integrating heterogeneous sources
should overcome the above challenges. We term such a strategy Interactogeneous.
We conducted cross-validation tests to assess the impact of network sources,
alternative path inclusion and confidence weights on the prioritization of
putative genes for 29 diseases. Heat diffusion ranking proved the best
prioritization method overall, increasing the gap to neighborhood and shortest
paths scores mostly on single source networks. Heterogeneous associations
consistently delivered superior performance over single source data across the
majority of methods. Results on the contribution of confidence weights were
inconclusive. Finally, the best Interactogeneous strategy, heat diffusion
ranking and associations from the STRING database, was used to prioritize genes
for Parkinson's disease. This method effectively recovered known genes and
uncovered interesting candidates which could be linked to pathogenic mechanisms
of the disease.
DOI: 10.1371/journal.pone.0049634
PMCID: PMC3501465
PMID: 23185389 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/24076290 | 1. J Am Coll Cardiol. 2014 Jan 28;63(3):259-66. doi: 10.1016/j.jacc.2013.07.091.
Epub 2013 Sep 25.
A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular
fibrillation in childhood and adolescence.
Marsman RF(1), Barc J(2), Beekman L(1), Alders M(3), Dooijes D(4), van den
Wijngaard A(5), Ratbi I(6), Sefiani A(6), Bhuiyan ZA(7), Wilde AA(8), Bezzina
CR(9).
Author information:
(1)Department of Clinical and Experimental Cardiology, Academic Medical Center,
Amsterdam, the Netherlands.
(2)Department of Clinical and Experimental Cardiology, Academic Medical Center,
Amsterdam, the Netherlands; ICIN-Netherlands Heart Institute, Utrecht, the
Netherlands.
(3)Department of Clinical Genetics, Academic Medical Center, Amsterdam, the
Netherlands.
(4)Department of Medical Genetics, University Medical Center Utrecht, Utrecht,
the Netherlands.
(5)Department of Clinical Genetics, Cardiovascular Research Institute
Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands.
(6)Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université
Mohamed V Souissi, Rabat, Morocco.
(7)Department of Clinical Genetics, Academic Medical Center, Amsterdam, the
Netherlands; Laboratoire de Génétique Moléculaire, Service de Génétique
Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne,
Switzerland.
(8)Department of Clinical and Experimental Cardiology, Academic Medical Center,
Amsterdam, the Netherlands; Princess Al Jawhara Albrahim Centre of Excellence in
Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi
Arabia.
(9)Department of Clinical and Experimental Cardiology, Academic Medical Center,
Amsterdam, the Netherlands. Electronic address: [email protected].
Comment in
J Am Coll Cardiol. 2014 Jan 28;63(3):267-8. doi: 10.1016/j.jacc.2013.07.089.
OBJECTIVES: This study aimed to identify the genetic defect in a family with
idiopathic ventricular fibrillation (IVF) manifesting in childhood and
adolescence.
BACKGROUND: Although sudden cardiac death in the young is rare, it frequently
presents as the first clinical manifestation of an underlying inherited
arrhythmia syndrome. Gene discovery for IVF is important as it enables the
identification of individuals at risk, because except for arrhythmia, IVF does
not manifest with identifiable clinical abnormalities.
METHODS: Exome sequencing was carried out on 2 family members who were both
successfully resuscitated from a cardiac arrest.
RESULTS: We characterized a family presenting with a history of ventricular
fibrillation (VF) and sudden death without electrocardiographic or
echocardiographic abnormalities at rest. Two siblings died suddenly at the ages
of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac
arrest with documented VF at ages 10 and 16 years, respectively. Exome
sequencing identified a missense mutation affecting a highly conserved residue
(p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried
by 1 of the siblings who died suddenly, from whom DNA was available. The
mutation was present in the mother and in another sibling, both asymptomatic but
displaying a marginally prolonged QT interval during exercise.
CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in
childhood and adolescence. The causality of the mutation is supported by
previous studies demonstrating that F90 mediates the direct interaction of CaM
with target peptides. Our approach highlights the utility of exome sequencing in
uncovering the genetic defect even in families with a small number of affected
individuals.
Copyright © 2014 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2013.07.091
PMID: 24076290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21185823 | 1. Eur J Pharmacol. 2011 Mar 11;654(3):258-65. doi: 10.1016/j.ejphar.2010.12.005.
Epub 2010 Dec 24.
Role of prostanoid IP and EP receptors in mediating vasorelaxant responses to
PGI2 analogues in rat tail artery: Evidence for Gi/o modulation via EP3
receptors.
Orie NN(1), Clapp LH.
Author information:
(1)BHF Laboratories, Department of Medicine, University College London, 5
University Street, London, WC1E 6JF, UK. [email protected]
Prostanoid IP receptors coupled to Gs are thought to be the primary target for
prostacyclin (PGI(2)) analogues. However, these agents also activate prostanoid
EP(1-4) receptor subtypes to varying degrees, which are positively (EP(2/4)) or
negatively (EP(3)) coupled to adenylate cyclase through Gs or Gi, respectively.
We investigated the role of these receptors in modulating relaxation to PGI(2)
analogues cicaprost, iloprost and treprostinil in pre-contracted segments of rat
tail artery. Prostanoid IP (RO1138452), EP(4) (GW627368X), EP(3) (L-798106),
EP(1-3) (AH6809), and EP(1) (SC-51322) receptor antagonists were used to
determine each receptor contribution. The role of G(i/o) was investigated using
pertussis toxin (PTX), while dependence on cAMP was determined using adenylate
cyclase (2'5'dideoxyadenosine, DDA) and protein kinase A
(2'-O-monobutyryladenosine- 3',5'-cyclic monophosphorothioate, Rp- isomer,
Rp-2'-O-MB-cAMPS) inhibitors, and by measurement of tissue cAMP. All analogues
caused relaxation which was significantly (P<0.01) inhibited by RO1138452; with
maximum response to cicaprost, iloprost and treprostinil reduced by 51%, 66% and
37%, respectively. GW627368X had no effect when used alone, but in combination
with RO1138452, caused a rightward shift of the curves for cicaprost and
iloprost but not treprostinil. PTX treatment potentiated relaxation to all 3
analogues (P<0.01), as did L798106 and AH6809 but not SC-51322. Basal cAMP
levels were higher in PTX-treated tissues and DDA- and
Rp-2'-O-MB-cAMPs--sensitive responses increased to analogue concentrations
<0.1μM. In conclusion, prostanoid EP(3) receptors via G(i/o) negatively modulate
prostanoid IP receptor-mediated relaxation to cicaprost, iloprost and
treprostinil. However, other pathways contribute to analogue-induced
vasorelaxation, the nature of which remains unclear for treprostinil.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2010.12.005
PMID: 21185823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23227859 | 1. Int J Neurosci. 2013 Apr;123(4):283-5. doi: 10.3109/00207454.2012.756485. Epub
2013 Feb 4.
A case of restless leg syndrome in a family with LRRK2 gene mutation.
De Rosa A(1), Guacci A, Peluso S, Del Gaudio L, Massarelli M, Barbato S,
Criscuolo C, De Michele G.
Author information:
(1)Department of Neurological Sciences, Federico II University, Naples, Italy.
anna [email protected]
LRRK2 gene mutations (PARK8) are a common cause of genetic Parkinson disease
(PD). G2019S, the most frequent mutation, is responsible for both familial and
sporadic cases of PD. The clinical picture is usually indistinguishable from
that observed in idiopathic PD; however, a wide range of clinical presentations
and pathological findings has been described. Restless leg syndrome (RLS) is a
disabling sleep-related sensorimotor disorder whose pathogenesis is likely
related to dopaminergic dysfunction. We report a 77-year-old woman with RLS and
familial history of parkinsonism. The father, one sister, two cousins and one
uncle were affected by PD. The proband and her sister were analyzed for
mutations in LRRK2 gene and resulted to carry one heterozygous G2019S mutation
in LRRK2 gene. The association between RLS and LRRK2 gene mutation may be
casual, but it can hypothesized that RLS is a possible phenotypic presentation
in PARK8.
DOI: 10.3109/00207454.2012.756485
PMID: 23227859 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23023959 | 1. Am J Med Genet A. 2012 Nov;158A(11):2733-42. doi: 10.1002/ajmg.a.35681. Epub
2012 Sep 28.
Meier-Gorlin syndrome: growth and secondary sexual development of a
microcephalic primordial dwarfism disorder.
de Munnik SA(1), Otten BJ, Schoots J, Bicknell LS, Aftimos S, Al-Aama JY, van
Bever Y, Bober MB, Borm GF, Clayton-Smith J, Deal CL, Edrees AY, Feingold M,
Fryer A, van Hagen JM, Hennekam RC, Jansweijer MC, Johnson D, Kant SG, Opitz JM,
Ramadevi AR, Reardon W, Ross A, Sarda P, Schrander-Stumpel CT, Sluiter AE,
Temple IK, Terhal PA, Toutain A, Wise CA, Wright M, Skidmore DL, Samuels ME,
Hoefsloot LH, Knoers NV, Brunner HG, Jackson AP, Bongers EM.
Author information:
(1)Department of Human Genetics, Institute for Genetic and Metabolic Disease,
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized
by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently,
mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of
the pre-replication complex, have been identified. This complex is essential for
DNA replication and therefore mutations are expected to impair cell
proliferation and consequently could globally reduce growth. However, detailed
growth characteristics of MGS patients have not been reported, and so this is
addressed here through study of 45 MGS patients, the largest cohort worldwide.
Here, we report that growth velocity (length) is impaired in MGS during
pregnancy and first year of life, but, thereafter, height increases in
paralleled normal reference centiles, resulting in a mean adult height of -4.5
standard deviations (SD). Height is dependent on ethnic background and
underlying molecular cause, with ORC1 and ORC4 mutations causing more severe
short stature and microcephaly. Growth hormone therapy (n = 9) was generally
ineffective, though in two patients with significantly reduced IGF1 levels,
growth was substantially improved by GH treatment, with 2SD and 3.8 SD
improvement in height. Growth parameters for monitoring growth in future MGS
patients are provided and as well we highlight that growth is disproportionately
affected in certain structures, with growth related minor genital abnormalities
(42%) and mammary hypoplasia (100%) frequently present, in addition to
established effects on ears and patellar growth.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.35681
PMID: 23023959 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17112502 | 1. Eur J Pharmacol. 2007 Jan 19;555(1):54-60. doi: 10.1016/j.ejphar.2006.10.005.
Epub 2006 Oct 17.
K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes
and attenuates an increase in repolarization.
Hasumi H(1), Matsuda R, Shimamoto K, Hata Y, Kaneko N.
Author information:
(1)Department of Cardiology and Pneumology, Dokkyo Medical University School of
Medicine 880 Kitakobayashi, Mibu, Tochigi, Japan.
K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong
cardioprotective action and acts as a multiple-channel blocker, including as a
K+ channel blocker. An experimental model of prolongation of the QT interval and
torsades de pointes can be induced in rabbits by treatment with clofilium in the
presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we
examined the effects of K201 with and without methoxamine on the QT and QTc
intervals, and determined whether K201 inhibits clofilium-induced torsades de
pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74).
Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without
methoxamine prolonged the QT interval in a dose-dependent manner, and torsades
de pointes did not occur in any animals. However, clofilium (50 microg/kg/min)
with methoxamine induced torsades de pointes in all animals (6/6). Torsades de
pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0,
50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades
de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited
clofilium-induced torsades de pointes and attenuated the increase of
repolarization caused by clofilium; the inhibitory effects of K201 may be
related to its pharmacological properties as an alpha1-adrenoceptor blocker.
Overall, our results show that K201 causes prolongation of the QT and QTc
intervals, but does not induce torsades de pointes, with and without
alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced
torsades de pointes, despite QT prolongation, suggesting that QT prolongation
alone is not a proarrhythmic signal.
DOI: 10.1016/j.ejphar.2006.10.005
PMID: 17112502 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20005733 | 1. Trends Endocrinol Metab. 2010 Apr;21(4):230-6. doi: 10.1016/j.tem.2009.11.008.
Epub 2009 Dec 11.
Novel neural pathways for metabolic effects of thyroid hormone.
Fliers E(1), Klieverik LP, Kalsbeek A.
Author information:
(1)Department of Endocrinology and Metabolism, Academic Medical Center,
University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
[email protected]
The relation between thyrotoxicosis, the clinical syndrome resulting from
exposure to excessive thyroid hormone concentrations, and the sympathetic
nervous system remains enigmatic. Nevertheless, beta-adrenergic blockers are
widely used to manage severe thyrotoxicosis. Recent experiments show that the
effects of thyrotoxicosis on hepatic glucose production and insulin sensitivity
can be modulated by selective hepatic sympathetic and parasympathetic
denervation. Indeed, thyroid hormone stimulates hepatic glucose production via a
sympathetic pathway, a novel central pathway for thyroid hormone action. Rodent
studies suggest that similar neural routes exist for thyroid hormone analogues
(e.g. thyronamines). Further elucidation of central effects of thyroid hormone
on autonomic outflow to metabolic organs, including the thyroid and brown
adipose tissue, will add to our understanding of hyperthyroidism.
Copyright 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tem.2009.11.008
PMID: 20005733 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23664178 | 1. Bioresour Technol. 2013 Oct;145:307-12. doi: 10.1016/j.biortech.2013.01.054.
Epub 2013 Jan 18.
Engineering strategies for simultaneous enhancement of C-phycocyanin production
and CO2 fixation with Spirulina platensis.
Chen CY(1), Kao PC, Tsai CJ, Lee DJ, Chang JS.
Author information:
(1)University Center for Bioscience and Biotechnology, National Cheng Kung
University, Tainan, Taiwan. [email protected]
Spirulina platensis produces nutraceutical product C-phycocyanin (C-PC) and
simultaneously mitigates CO2 emissions during its growth. Using a designed
flat-type photobioreactor, the S. platensis biomass production was markedly
enhanced, leading to a CO2 removal rate and a biomass concentration of 0.23
g/L/d and 2.25 g/L, respectively. The cell growth, CO2 fixation rate and C-PC
production of S. platensis were investigated when it was cultivated under
different irradiation conditions. As the light intensity increased from 100 to
700 μmol/m(2)/s, the overall biomass productivity, CO2 consumption rate and
maximal C-PC productivity increased significantly to 0.74, 1.53 and 0.11 g/L/d,
respectively. After determining the suitable light intensity, the nitrogen
concentration was also adjusted to further enhance the performance of CO2
fixation and C-PC production. The results show that with an optimal nitrogen
concentration of 0.045 M, the CO2 consumption rate and maximal C-PC productivity
were further increased to 1.58 and 0.13 g/L/d, respectively.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.biortech.2013.01.054
PMID: 23664178 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15341676 | 1. Curr Treat Options Oncol. 2004 Oct;5(5):377-89. doi:
10.1007/s11864-004-0028-0.
Alternatives to cytology in the management of non-muscle invasive bladder
cancer.
Amiel GE(1), Shu T, Lerner SP.
Author information:
(1)Baylor College of Medicine, 6560 Fannin Street, Suite 2100, Houston, TX
77030, USA.
The natural history of non-muscle invasive bladder cancer is characterized by a
high probability of recurrence and in the case of high-grade tumors, progression
to muscle invasive cancer. This mandates a follow-up strategy designed to
identify recurrences in the bladder early in their evolution in order to
facilitate early intervention and ablation. Urine cytology is considered the
gold standard urine biomarker. Although specificity exceeds 90% to 95%, its
overall sensitivity ranges from 40% to 60% in expert hands and is both tumor
grade and operator dependent. While cytology is an excellent test for detection
of high-grade disease, the sensitivity is particularly weak for the detection of
low grade tumors. This has spawned an entire field of research of in vitro
diagnostic tests and cell-based assays in order to improve the diagnostic
accuracy for detection of incident or recurrent disease. To date, the US Food
and Drug Administration approved dipstick and immunoassays marketed as
point-of-care tests. The point-of-care tests are intended for use as an adjunct
to cystoscopy and cytology, and may have a role in the office evaluation of
hematuria patients. Monoclonal antibody-based tests combined with cytology may
improve the diagnostic accuracy and are superior to cytology alone. A recently
approved cell-based assay, utilizing fluorescent in situ hybridization
technology, may help resolve suspicious cytologies, and provide early and
additional information about the biology of the bladder urothelium beyond that
provided by cytology, a marker of disease relatively late in evolution. Novel
promising markers are in various stages of clinical testing, and a panel of
biomarkers may serve in the future as a feasible alternative to urine cytology
and cystoscopy for the screening, detection, and follow-up of non-muscle
invasive bladder cancer.
DOI: 10.1007/s11864-004-0028-0
PMID: 15341676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18266676 | 1. J Cardiovasc Electrophysiol. 2008 May;19(5):510-5. doi:
10.1111/j.1540-8167.2007.01081.x. Epub 2008 Feb 4.
X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by
emerin mutation.
Karst ML(1), Herron KJ, Olson TM.
Author information:
(1)Department of Medicine, Division of Cardiovascular Diseases, and Pediatric
and Adolescent Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota
55905, USA.
Comment in
J Cardiovasc Electrophysiol. 2008 May;19(5):516-8. doi:
10.1111/j.1540-8167.2007.01097.x.
INTRODUCTION: Atrial fibrillation (AF) is a heritable disorder with male
predilection, suggesting a sex chromosome defect in certain patients.
Loss-of-function truncation mutations in EMD, encoding the nuclear membrane
protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD)
characterized by localized contractures and skeletal myopathy in adolescence,
sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a
variably associated trait. This study sought to identify the genetic basis for
male-restricted, nonsyndromic sinus node dysfunction and AF in a
multigenerational family.
METHODS AND RESULTS: Genealogical and medical records, and DNA samples, were
obtained. Progressive SND and AF occurred in four males related through maternal
lineages, consistent with X-linked inheritance. Skeletal myopathy was absent,
even at advanced ages. Targeted X chromosome genotyping mapped the disease locus
to Xq28, implicating EMD as a positional candidate gene. DNA sequencing revealed
hemizygosity for an in-frame 3-bp deletion in EMD (Lys37del) in affected males,
disrupting a residue within the LEM binding domain critical for nuclear assembly
but leaving the remainder of the protein intact. Buccal epithelial cell staining
with emerin antibody demonstrated near-total functional loss of emerin. Female
relatives underwent prospective electrocardiographic and genetic testing. Those
heterozygous for Lys37del had approximately 50-70% emerin-positive nuclei and
variable degrees of paroxysmal supraventricular arrhythmia.
CONCLUSIONS: Mutation of EMD can underlie X-linked familial AF. Lys37del is
associated with epithelial cell emerin deficiency, as in EDMD, yet it causes
electrical atriomyopathy in the absence of skeletal muscle disease. Targeted
genetic testing of EMD should be considered in patients with SND-associated AF
and/or family history suggesting X-linked inheritance.
DOI: 10.1111/j.1540-8167.2007.01081.x
PMCID: PMC2367157
PMID: 18266676 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15453048 | 1. Tunis Med. 2004 May;82(5):453-6.
[Gaucher's disease uncovered late].
[Article in French]
Ben Said F(1), Mseddi S, Ben Aribia N, Elloumi M, Ben Jemaa M, Ben Amar M,
Boudawara T, Kallel C, Makni F, Souissi T.
Author information:
(1)Service et Laboratoire d'hématologie, CHU Hédi Chaker SFAX.
Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a
deficient activity of the lysosomal enzyme beta glucocerebrosidase. This disease
is usually diagnosed in the first or second decade of life with the arising of
bone pains, splenomegaly and hemorragic manifestations due to thrombocytopenia.
When the enlarged spleen is not evident, or after splenectomy, patients may be
mis-identified as having Gaucher's disease. We present here two cases of elderly
patients aged 70 and 46 years respectively, in whom the disease was a surprising
finding of bone marrow examination, during check up for pancytopenia.
PMID: 15453048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25429104 | 1. J Biol Chem. 2015 Jan 9;290(2):744-54. doi: 10.1074/jbc.M114.610584. Epub 2014
Nov 26.
Structural features of membrane-bound glucocerebrosidase and α-synuclein probed
by neutron reflectometry and fluorescence spectroscopy.
Yap TL(1), Jiang Z(1), Heinrich F(2), Gruschus JM(1), Pfefferkorn CM(1), Barros
M(3), Curtis JE(4), Sidransky E(5), Lee JC(6).
Author information:
(1)From the Laboratory of Molecular Biophysics, NHLBI, and.
(2)the Department of Physics, Carnegie Mellon University, Pittsburgh,
Pennsylvania 15213, and the Center for Neutron Research, National Institute of
Standards and Technology (NIST), Gaithersburg, Maryland 20899.
(3)the Department of Physics, Carnegie Mellon University, Pittsburgh,
Pennsylvania 15213, and.
(4)the Center for Neutron Research, National Institute of Standards and
Technology (NIST), Gaithersburg, Maryland 20899.
(5)the Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda,
Maryland 20892.
(6)From the Laboratory of Molecular Biophysics, NHLBI, and [email protected].
Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher
disease, are a common genetic risk factor for the development of Parkinson
disease and related disorders, implicating the role of this lysosomal hydrolase
in the disease etiology. A specific physical interaction exists between the
Parkinson disease-related protein α-synuclein (α-syn) and GCase both in solution
and on the lipid membrane, resulting in efficient enzyme inhibition. Here,
neutron reflectometry was employed as a first direct structural characterization
of GCase and α-syn·GCase complex on a sparsely-tethered lipid bilayer, revealing
the orientation of the membrane-bound GCase. GCase binds to and partially
inserts into the bilayer with its active site most likely lying just above the
membrane-water interface. The interaction was further characterized by intrinsic
Trp fluorescence, circular dichroism, and surface plasmon resonance
spectroscopy. Both Trp fluorescence and neutron reflectometry results suggest a
rearrangement of loops surrounding the catalytic site, where they extend into
the hydrocarbon chain region of the outer leaflet. Taking advantage of
contrasting neutron scattering length densities, the use of deuterated α-syn
versus protiated GCase showed a large change in the membrane-bound structure of
α-syn in the complex. We propose a model of α-syn·GCase on the membrane,
providing structural insights into inhibition of GCase by α-syn. The interaction
displaces GCase away from the membrane, possibly impeding substrate access and
perturbing the active site. GCase greatly alters membrane-bound α-syn, moving
helical residues away from the bilayer, which could impact the degradation of
α-syn in the lysosome where these two proteins interact.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M114.610584
PMCID: PMC4295019
PMID: 25429104 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23382987 | 1. PLoS One. 2013;8(1):e54848. doi: 10.1371/journal.pone.0054848. Epub 2013 Jan
29.
A phylogeny of birds based on over 1,500 loci collected by target enrichment and
high-throughput sequencing.
McCormack JE(1), Harvey MG, Faircloth BC, Crawford NG, Glenn TC, Brumfield RT.
Author information:
(1)Museum of Natural Science, Louisiana State University, Baton Rouge,
Louisiana, USA. [email protected]
Evolutionary relationships among birds in Neoaves, the clade comprising the vast
majority of avian diversity, have vexed systematists due to the ancient, rapid
radiation of numerous lineages. We applied a new phylogenomic approach to
resolve relationships in Neoaves using target enrichment (sequence capture) and
high-throughput sequencing of ultraconserved elements (UCEs) in avian genomes.
We collected sequence data from UCE loci for 32 members of Neoaves and one
outgroup (chicken) and analyzed data sets that differed in their amount of
missing data. An alignment of 1,541 loci that allowed missing data was 87%
complete and resulted in a highly resolved phylogeny with broad agreement
between the Bayesian and maximum-likelihood (ML) trees. Although results from
the 100% complete matrix of 416 UCE loci were similar, the Bayesian and ML trees
differed to a greater extent in this analysis, suggesting that increasing from
416 to 1,541 loci led to increased stability and resolution of the tree. Novel
results of our study include surprisingly close relationships between
phenotypically divergent bird families, such as tropicbirds (Phaethontidae) and
the sunbittern (Eurypygidae) as well as between bustards (Otididae) and turacos
(Musophagidae). This phylogeny bolsters support for monophyletic waterbird and
landbird clades and also strongly supports controversial results from previous
studies, including the sister relationship between passerines and parrots and
the non-monophyly of raptorial birds in the hawk and falcon families. Although
significant challenges remain to fully resolving some of the deep relationships
in Neoaves, especially among lineages outside the waterbirds and landbirds, this
study suggests that increased data will yield an increasingly resolved avian
phylogeny.
DOI: 10.1371/journal.pone.0054848
PMCID: PMC3558522
PMID: 23382987 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/3086870 | 1. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3924-8. doi:
10.1073/pnas.83.11.3924.
Genes encoding major light-harvesting polypeptides are clustered on the genome
of the cyanobacterium Fremyella diplosiphon.
Conley PB, Lemaux PG, Lomax TL, Grossman AR.
The polypeptide composition of the phycobilisome, the major light-harvesting
complex of prokaryotic cyanobacteria and certain eukaryotic algae, can be
modulated by different light qualities in cyanobacteria exhibiting chromatic
adaptation. We have identified genomic fragments encoding a cluster of
phycobilisome polypeptides (phycobiliproteins) from the chromatically adapting
cyanobacterium Fremyella diplosiphon using previously characterized DNA
fragments of phycobiliprotein genes from the eukaryotic alga Cyanophora paradoxa
and from F. diplosiphon. Characterization of two lambda-EMBL3 clones containing
overlapping genomic fragments indicates that three sets of phycobiliprotein
genes--the alpha- and beta-allophycocyanin genes plus two sets of alpha- and
beta-phycocyanin genes--are clustered within 13 kilobases on the cyanobacterial
genome and transcribed off the same strand. The gene order
(alpha-allophycocyanin followed by beta-allophycocyanin and beta-phycocyanin
followed by alpha-phycocyanin) appears to be a conserved arrangement found
previously in a eukaryotic alga and another cyanobacterium. We have reported
that one set of phycocyanin genes is transcribed as two abundant red
light-induced mRNAs (1600 and 3800 bases). We now present data showing that the
allophycocyanin genes and a second set of phycocyanin genes are transcribed into
major mRNAs of 1400 and 1600 bases, respectively. These transcripts are present
in RNA isolated from cultures grown in red and green light, although lower
levels of the 1600-base phycocyanin transcript are present in cells grown in
green light. Furthermore, a larger transcript of 1750 bases hybridizes to the
allophycocyanin genes and may be a precursor to the 1400-base species.
DOI: 10.1073/pnas.83.11.3924
PMCID: PMC323637
PMID: 3086870 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12424964 | 1. Rinsho Shinkeigaku. 2002 Feb;42(2):140-4.
[The first Japanese case of autosomal dominant Emery-Dreifuss muscular dystrophy
with a novel mutation in the lamin A/C gene].
[Article in Japanese]
Onishi Y(1), Higuchi J, Ogawa T, Namekawa A, Hayashi H, Odakura H, Goto K,
Hayashi YK.
Author information:
(1)Department of Neurology, Sendai City Hospital.
Emery-Dreifuss muscular dystrophy (EDMD) is a muscular disorder characterized by
1) early contracture of the elbows. Achilles tendons and post-cervical muscles,
2) slowly progressive muscle wasting and weakness with a humeroperoneal
distribution, and 3) life-threatening cardiomyopathy with conduction block. Most
of families with EDMD show X-linked recessive inheritance with mutations in the
STA gene on chromosome Xq28, which encodes a protein named emerin. A rare
autosomal dominant form of EDMD (AD-EDMD) is caused by mutations in lamin A/C
gene (LMNA) on chromosome 1q21. Both emerin and lamin A/C are located in the
inner surface membrane of the nucleus. A 49-year-old woman was skinny and slow
runner from childhood and suspected as having a certain muscular disorder. At 35
years, she was found to have the second degree atrioventricular block. At 45
years, she was admitted to a hospital for right-side hemiplegia after cerebral
infarction. Cardiac involvement was also observed including high degree
atrioventricular block with chronic atrial fibrillation and frequent paroxysmal
ventricular contraction on the electrocardiogram. At 49 years, she was referred
to our hospital for further evaluation. She had possible dilated cardiomyopathy
with conduction block. She also had muscular atrophy and weakness in all
extremities, predominantly in the right-side, and contracture of bilateral
Achilles tendon, knee and elbow joints, and postcervical muscles. Biopsied
skeletal muscle and electromyogram showed myopathic changes. Since a novel point
mutation of Ser303Pro was found in exon 5 of LMNA gene, she was diagnosed as
having AD-EDMD and had a permanent pacemaker implantation. Her daughter also had
some abnormalities on electrocardiogram. This is the first Japanese case of
AD-EDMD. Amiodaron was effective for non-sustained ventricular tachycardia.
Early diagnosis and following cardiological examinations and treatments are
important and necessary to improve the prognosis of the patients with EDMD.
PMID: 12424964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22433611 | 1. Ann Pharmacother. 2012 Apr;46(4):590-8. doi: 10.1345/aph.1Q538. Epub 2012 Mar
20.
Dapagliflozin for the treatment of type 2 diabetes.
Anderson SL(1), Marrs JC.
Author information:
(1)University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences,
Aurora, CO, USA. [email protected]
OBJECTIVE: To review the literature and describe the pharmacologic,
pharmacokinetic, and pharmacodynamic properties; clinical safety; and efficacy
of dapagliflozin, a new drug currently under review by the Food and Drug
Administration (FDA) for the treatment of type 2 diabetes.
DATA SOURCES: A MEDLINE (1995-November 2011) and ClinicalTrials.gov search was
conducted using the terms dapagliflozin, sodium-glucose cotransporter 2
inhibitor, and SGLT2 inhibitor. Reference citations from publications identified
were also reviewed.
STUDY SELECTION AND DATA EXTRACTION: All English-language studies, including
abstracts, evaluating dapagliflozin use in humans were included in this review.
DATA SYNTHESIS: Dapagliflozin is the first-in-class oral sodium-glucose
cotransporter 2 (SGLT2) inhibitor that represents a new potential therapeutic
option for the treatment of type 2 diabetes mellitus. Its mechanism of action is
insulin- and insulin-sensitivity independent. Preliminary data suggest that
dapagliflozin decreases hemoglobin A(1c), fasting plasma glucose, and
postprandial plasma glucose, while also promoting weight loss. In Phase 1, 2,
and 3 clinical trials, dapagliflozin has exhibited a safety and tolerability
profile similar to that of placebo.
CONCLUSIONS: Dapagliflozin is a novel oral antihyperglycemic agent that has
demonstrated promise as monotherapy and as synergistic combination therapy with
currently available agents in Phase 3 clinical trials. On January 19, 2012, the
FDA issued a complete response letter to AstraZeneca and Bristol-Myers Squibb
regarding the new drug application for dapagliflozin. The FDA is requesting
additional clinical data-from ongoing studies and potentially new clinical
trials-to better describe the risk-benefit profile of the drug. Both
manufacturers remain committed to the development of dapagliflozin, and there
are currently 8 Phase 3 trials ongoing. Dapagliflozin has the potential to be
the next new oral agent in the diabetes drug armamentarium.
DOI: 10.1345/aph.1Q538
PMID: 22433611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8574597 | 1. New Horiz. 1995 Nov;3(4):669-79.
The immune system in uremia and during its treatment.
Haag-Weber M(1), Hörl WH.
Author information:
(1)Department of Medicine, University of Vienna, Austria.
Infectious complications are frequent and often lethal in patients with uremia.
Serious alterations in neutrophil function, e.g., phagocytosis, mononuclear cell
activation, cytokine production, complement activation, T-cell function, and
adhesion molecule expression, have been documented in uremic patients. Uremia
per se is a cause of some of these derangements, but much evidence now exists
that blood-membrane interaction during dialysis is responsible for many of these
abnormalities. This is particularly true when bio-incompatible cellulose-based
membranes are used. In many of these patients, newly described granulocyte
inhibitory proteins (GIP) can be demonstrated. These two proteins, GIP I and II
(28 kD and 9.5 kD, respectively, in molecular weight), block effective bacterial
killing, chemotaxis, and oxygen metabolism. It appears that GIP I is a member of
the lightchain family, and GIP II is the advanced glycosilation end product of
beta 2-microglobulin. Another inhibitory protein, degranulation inhibitory
protein (DIP), has been isolated. This protein is 14 kD in molecular weight, and
is identical to the angioplastic factor angiogenin. DIP levels are significantly
elevated in patients undergoing dialysis. Much still needs to be learned about
the interactions of these inhibitory proteins with other soluble inflammatory
mediators and, in particular, cytokines. It is clear, however, that profound
derangements in immune function take place during uremia and dialytic therapy.
Such derangements are likely to play an important role in determining the rate
of recovery of renal function and the patient's ability to respond to septic
insults. Further insights into the pathogenesis of uremic-dialytic immune
dysfunction are already yielding improved patient management and decreased
infection rates.
PMID: 8574597 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25564661 | 1. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):E297-302. doi:
10.1073/pnas.1424028112. Epub 2015 Jan 6.
Inflammation-sensitive super enhancers form domains of coordinately regulated
enhancer RNAs.
Hah N(1), Benner C(2), Chong LW(1), Yu RT(1), Downes M(1), Evans RM(3).
Author information:
(1)Gene Expression Laboratory.
(2)Razzavi Newman Integrated Genomics and Bioinformatics Core, and.
(3)Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk
Institute for Biological Studies, La Jolla, CA 92037 [email protected].
Enhancers are critical genomic elements that define cellular and functional
identity through the spatial and temporal regulation of gene expression. Recent
studies suggest that key genes regulating cell type-specific functions reside in
enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here
we report that enhancer RNAs (eRNAs) identified by global nuclear run-on
sequencing are extensively transcribed within super enhancers and are
dynamically regulated in response to cellular signaling. Using Toll-like
receptor 4 (TLR4) signaling in macrophages as a model system, we find that
transcription of super enhancer-associated eRNAs is dynamically induced at most
of the key genes driving innate immunity and inflammation. Unexpectedly, genes
repressed by TLR4 signaling are also associated with super enhancer domains and
accompanied by massive repression of eRNA transcription. Furthermore, we find
each super enhancer acts as a single regulatory unit within which eRNA and genic
transcripts are coordinately regulated. The key regulatory activity of these
domains is further supported by the finding that super enhancer-associated
transcription factor binding is twice as likely to be conserved between human
and mouse than typical enhancer sites. Our study suggests that transcriptional
activities at super enhancers are critical components to understand the dynamic
gene regulatory network.
DOI: 10.1073/pnas.1424028112
PMCID: PMC4311831
PMID: 25564661 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/7620118 | 1. Semin Cell Biol. 1995 Feb;6(1):21-8. doi: 10.1016/1043-4682(95)90011-x.
Huntington's disease.
Gusella JF(1), MacDonald ME.
Author information:
(1)Molecular Neurogenetics Unit, Massachusetts General Hospital East,
Charlestown 02129, USA.
Early in 1993, an unstable, expanded trinucleotide repeat in a novel gene of
unknown function was identified on HD chromosomes. This discovery unleased a
flurry of experimentation that has established the expanded CAG repeat the
almost universal cause of the characteristic neurologic symptoms and pathology
of this neurodegenerative disorder of midlife onset. The biochemical basis for
the specific neuronal loss of HD remains uncertain, but the genetic lesion
probably acts via its consequent polyglutamine segment in the protein product,
huntingtin. This review will describe the basic parameters of the HD repeat's
behavior and the knowledge that has accumulated concerning its potential
mechanisms of action.
DOI: 10.1016/1043-4682(95)90011-x
PMID: 7620118 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16235537 | 1. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 Sep;36(5):683-5.
[Association between phospholamban gene mutation and dilated cardiomyopathy in
the Chengdu area].
[Article in Chinese]
Chen XY(1), Rao L, Zhou B, Zhang L, Chen H, Wang YP, Wang B.
Author information:
(1)Department of Cardiology, West China Hospital, Sichuan University, Chengdu
610041, China.
OBJECTIVE: To find out whether phospholamban (PLN) is the virulence gene of
dilated cardiomyopathy (DCM) in the Chinese of Chengdu.
METHODS: DNA was isolated from 89 hospitalized unrelated patients with DCM and
110 healthy Chinese Hans as controls. The PLN mutations was screened by
polymerase chain reaction (PCR)-single strand conformation polymorphisms (SSCP)
and nucleotide sequence analysis.
RESULTS: In polyacrylamide gel lectrophoresis, no abnormal conformer was found
in the two groups. In DNA sequence, no C --> T missense mutation at nucleotide
25 was identified in the DCM patients and the controls. Meanwhile, T --> G
missense mutation at nucleotide 116 was not found in the affected individuals
and in the controls.
CONCLUSION: No PLN gene mutation was found in patients with DCM in Chengdu. This
result indicated that PLN gene mutation may not be a common cause for DCM in the
Chinese population in Chengdu.
PMID: 16235537 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24073184 | 1. Transl Behav Med. 2013 Sep;3(3):320-5. doi: 10.1007/s13142-013-0206-3.
Mobile apps for pediatric obesity prevention and treatment, healthy eating, and
physical activity promotion: just fun and games?
Schoffman DE(1), Turner-McGrievy G, Jones SJ, Wilcox S.
Author information:
(1)Department of Health Promotion, Education, and Behavior, Arnold School of
Public Health, University of South Carolina, Columbia, SC 29208 USA.
Mobile applications (apps) offer a novel way to engage children in behavior
change, but little is known about content of commercially available apps for
this population. We analyzed the content of apps for iPhone/iPad for pediatric
weight loss, healthy eating (HE), and physical activity (PA). Fifty-seven apps
were downloaded and tested by two independent raters. Apps were coded for:
inclusion of the Expert Committee for Pediatric Obesity Prevention's (ECPOP)
eight recommended strategies (e.g., set goals) and seven behavioral targets
(e.g., do ≥1 h of PA per day), utilization of gaming elements, and general
characteristics. Most apps lacked any expert recommendations (n = 35, 61.4 %).
The mean number of recommendations among apps that used recommendations was
3.6 ± 2.7 out of 15, 56.1 % (n = 32) apps were classified as games, and mean
price per app was $1.05 ± 1.66. Most apps reviewed lacked expert recommendations
and could be strengthened by addition of comprehensive information about health
behavior change and opportunities for goal setting.
DOI: 10.1007/s13142-013-0206-3
PMCID: PMC3771006
PMID: 24073184 |
http://www.ncbi.nlm.nih.gov/pubmed/20589316 | 1. Thromb Haemost. 2010 Aug;104(2):302-10. doi: 10.1160/TH10-02-0097. Epub 2010
Jun 29.
Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human
platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa,
XIa and thrombin.
Wong PC(1), Jiang X.
Author information:
(1)Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey,
USA. [email protected]
Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in
late-stage clinical development. This study evaluated the in vitro effect of
apixaban on human platelet aggregation induced by thrombin derived via the
extrinsic pathway. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214),
thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for
comparison. Citrated human platelets-rich plasma (PRP) was treated with 50 mg/ml
corn trypsin inhibitor (to block the contact factor pathway) and 3 mM
H-Gly-Pro-Arg-Pro-OH-AcOH (to prevent fibrin polymerisation). Human tissue
factor (TF) (Innovin; dilution 1:1,000 to 1:1,500) plus 7.5 mM CaCl2 was added
to PRP pre-incubated with vehicle or increasing concentrations of inhibitors.
The TF-induced platelet aggregation was measured by optical aggregometry. TF
produced 85 +/- 3% aggregation of human platelets in the vehicle-treated group
(n=10). Apixaban and other factor inhibitors, except the FXIa inhibitor,
inhibited TF-induced platelet aggregation with IC50 (nM) values as follows: 4
+/- 1 (apixaban), 8 +/- 2 (rivaroxaban), 13 +/- 1 (BMS-593214), 46 +/- 1
(dabigatran) and 79 +/- 1 (argatroban). BMS-262084 (IC50 = 2.8 nM vs. human
FXIa) had no effect on TF-induced platelet aggregation at 10 microM. These
inhibitors at 10 microM had no effect on platelet aggregation induced by ADP and
collagen, as expected from their mechanism of action. This study demonstrates
that inhibition of thrombin generation by blocking upstream proteases (FVIIa and
FXa) in the blood coagulation cascade is as effective as direct thrombin
inhibition in preventing TF-induced platelet aggregation. Under these
experimental conditions, a FXIa inhibitor did not prevent TF-induced platelet
aggregation.
DOI: 10.1160/TH10-02-0097
PMID: 20589316 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24857652 | 1. Cell Rep. 2014 Jun 12;7(5):1443-1455. doi: 10.1016/j.celrep.2014.04.042. Epub
2014 May 22.
Transcription factor cooperativity in early adipogenic hotspots and
super-enhancers.
Siersbæk R(1), Rabiee A(1), Nielsen R(1), Sidoli S(1), Traynor S(1), Loft A(1),
Poulsen LC(1), Rogowska-Wrzesinska A(1), Jensen ON(1), Mandrup S(2).
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Southern
Denmark, 5230 Odense M, Denmark.
(2)Department of Biochemistry and Molecular Biology, University of Southern
Denmark, 5230 Odense M, Denmark. Electronic address: [email protected].
It is becoming increasingly clear that transcription factors operate in complex
networks through thousands of genomic binding sites, many of which bind several
transcription factors. However, the extent and mechanisms of crosstalk between
transcription factors at these hotspots remain unclear. Using a combination of
advanced proteomics and genomics approaches, we identify ∼12,000 transcription
factor hotspots (∼400 bp) in the early phase of adipogenesis, and we find
evidence of both simultaneous and sequential binding of transcription factors at
these regions. We demonstrate that hotspots are highly enriched in large
super-enhancer regions (several kilobases), which drive the early adipogenic
reprogramming of gene expression. Our results indicate that cooperativity
between transcription factors at the level of hotspots as well as
super-enhancers is very important for enhancer activity and transcriptional
reprogramming. Thus, hotspots and super-enhancers constitute important
regulatory hubs that serve to integrate external stimuli on chromatin.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2014.04.042
PMID: 24857652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20947659 | 1. Hum Mol Genet. 2011 Jan 1;20(1):202-10. doi: 10.1093/hmg/ddq454. Epub 2010 Oct
14.
Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene
in Europeans with Parkinson's disease.
Lesage S(1), Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, Viallet F,
Lohmann E, Corvol JC, Honoré A, Rivaud S, Vidailhet M, Dürr A, Brice A; French
Parkinson's Disease Genetics Study Group.
Collaborators: Agid Y, Bonnet AM, Borg M, Brice A, Broussolle E, Damier P,
Destée A, Dürr A, Durif F, Lesage S, Lohmann E, Martinez M, Pollak P, Rascol O,
Tison F, Tranchant C, Troiano A, Vérin M, Viallet F, Vidailhet M.
Author information:
(1)Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut
du Cerveau et de la Moelle épinière, UMR-S975, and Department of Genetics and
Cytogenetics, Pitié-Salpêtrière Hospital, Paris, France.
Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme
deficient in Gaucher's disease (GD) are associated with Parkinson's disease
(PD). To investigate the sequence variants, their association with PD and the
related phenotypes in a large cohort of European, mostly French, patients and
controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated
multiplex families, 605 patients with apparently sporadic PD and 391 ethnically
matched controls. GBA mutations were significantly more frequent (odds
ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients
(76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family
histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different
mutations were identified in patient and control groups, including seven novel
variants. N370S and L444P accounted for 70% of all mutant alleles in the patient
group. PD patients with GBA mutations more frequently had bradykinesia as the
presenting symptom and levodopa-induced dyskinesias. The phenotype was similar
in patients with one, two or complex GBA mutations, although the two patients
with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation
analyses in 21 multiplex families showed that 17% of the affected relatives did
not carry GBA mutations found in the given family, indicating heterogeneity of
the aetiology, but 46% of the unaffected relatives were GBA mutation carriers.
These genotype and clinical analyses on the largest homogeneous sample of
European patients studied to date confirmed that GBA mutations are the most
common genetic risk factor for PD, particularly in familial forms.
DOI: 10.1093/hmg/ddq454
PMID: 20947659 [Indexed for MEDLINE] |