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http://www.ncbi.nlm.nih.gov/pubmed/16479172 | 1. Cell Cycle. 2006 Feb;5(4):363-5. doi: 10.4161/cc.5.4.2475. Epub 2006 Feb 15.
The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma.
Uziel T(1), Zindy F, Sherr CJ, Roussel MF.
Author information:
(1)Department of Genetics & Tumor Cell Biology, St. Jude Children's Research
Hospital, Memphis, Tennessee 38105, USA.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor which is
thought to originate from cerebellar granule cell precursors (CGNPs) that fail
to properly exit the cell cycle and differentiate. Although mutations in the
Sonic Hedgehog (Shh) signaling pathway occur in 30% of cases, genetic
alterations that account for MB formation in most patients have not yet been
identified. We recently determined that the cyclin D-dependent kinase inhibitor,
p18(Ink4c), is expressed as CGNPs exit the cell cycle, suggesting that this
protein might play a central role in arresting the proliferation of these cells
and in timing their subsequent migration and differentiation. In mice,
disruption of Ink4c collaborates independently with loss of p53 or with
inactivation of the gene (Ptc1) encoding the Shh receptor, Patched, to induce MB
formation. Whereas loss of both Ink4c alleles is required for MB formation in a
p53-null background, Ink4c is haplo-insufficient for tumor suppression in a
Ptc(1+/-) background. Moreover, MBs derived from Ptc(1+/-) mice that lack one or
two Ink4c alleles retain wild-type p53. Methylation of the INK4C (CDKN2C)
promoter and complete loss of p18(INK4C) protein expression were detected in a
significant fraction of human MBs again pointing toward a role for INK4C in
suppression of MB formation.
DOI: 10.4161/cc.5.4.2475
PMID: 16479172 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12650976 | 1. Brain Res. 2003 Mar 28;967(1-2):152-60. doi: 10.1016/s0006-8993(02)04243-9.
Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders.
Krapfenbauer K(1), Engidawork E, Cairns N, Fountoulakis M, Lubec G.
Author information:
(1)F. Hoffman-La Roche, Basel, Switzerland.
An increasing body of evidence indicates that oxidative stress and damage play a
role in the pathogenesis of a number of diseases associated with
neurodegeneration, including Down syndrome (DS), Alzheimer's disease (AD) and
Pick's disease (PD). Although oxidative stress is a common element in these
diseases, specific clinico-pathological phenotypes have been described for each
disorder. Development of these phenotypes might be linked, among others, to
differences in antioxidant response. The present study is designed to
investigate expression of peroxiredoxins (Prxs), the newly characterized family
of highly conserved antioxidant enzymes, and other antioxidant enzymes in
frontal cortex and cerebellum of DS, AD and PD patients using the technique of
proteomics. Levels of Prx I, Mn superoxide dismutase (SOD2) and
glutathione-S-transferase omega1 in DS, AD and PD were not significantly
different from that of controls in both brain regions investigated. In contrast,
Prx II was significantly increased (P<0.05) in frontal cortex of DS, AD and PD,
whereas Prx III was decreased in frontal cortex of DS (P<0.01) and PD (P<0.001).
Interestingly, Prx VI displayed a significant increase (P<0.05) only in PD
frontal cortex. The present data indicate that differential regulation of
antioxidant enzymes exist in DS, AD and PD, suggestive of the diversity as well
as distinct functional roles of these proteins. Moreover, while up-regulation of
Prx II appears to provide evidence for the existence of compensatory response in
increased cell loss, up-regulation of Prx VI may be used to discriminate PD from
AD as well as DS.
DOI: 10.1016/s0006-8993(02)04243-9
PMID: 12650976 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8419325 | 1. J Biol Chem. 1993 Jan 15;268(2):1226-35.
Rod structure of a phycoerythrin II-containing phycobilisome. I. Organization
and sequence of the gene cluster encoding the major phycobiliprotein rod
components in the genome of marine Synechococcus sp. WH8020.
Wilbanks SM(1), Glazer AN.
Author information:
(1)Department of Molecular and Cell Biology, University of California, Berkeley
94720.
Phycobilisomes of the unicellular marine cyanobacteria are unique in having rod
substructures with two distinct phycoerythrins, PE I and PE II, with five and
six bilins, respectively (Ong, L. J., and Glazer, A. N. (1991) J. Biol. Chem.
266, 9515-9527). The genes for the alpha and beta subunits of PE I, PE II, and
phycocyanin, and that for the PE II-associated linker polypeptide, are clustered
on a single 15-kilobase region of the genome of Synechococcus sp. WH8020.
Complete sequencing of this region allowed definitive assignment of the
positions of all bilin attachment sites in these phycobiliproteins. Twelve other
open reading frames are closely associated with the structural genes specified
above. Six are homologous to open reading frames adjacent to phycobiliprotein
genes in other cyanobacteria and inferred to be involved in bilin addition. This
is the largest number of open reading frames of this class known in any
cyanobacterium. Another of the open reading frames has a short region of
striking similarity to the active site sequence of a bovine
protein-phosphotyrosine phosphatase.
PMID: 8419325 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23429937 | 1. Ann Surg Oncol. 2013 May;20(5):1668-75. doi: 10.1245/s10434-012-2733-4. Epub
2013 Feb 22.
Metastatic lymph node CHIP expression is a potential prognostic marker for
resected esophageal squamous cell carcinoma patients.
Wen J(1), Luo KJ, Hu Y, Yang H, Fu JH.
Author information:
(1)State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen
University, Guangzhou, People's Republic of China.
BACKGROUND: C-terminal Hsp-interacting protein (CHIP) is an HSP70 and HSP90
interacting co-chaperone and an E3 ubiquitin ligase. Previous studies have
reported the role of CHIP in cancer progression by targeting protein
degradation. However, its role and clinical significance in esophageal squamous
cell carcinoma (ESCC) has not been elucidated. We investigated the correlation
of CHIP expression and clinical outcome in a group of T3N1-3M0 surgically
resected ESCCs.
METHODS: Tissue microarrays constructed of 234 surgically resected T3N1-3M0 ESCC
primary tumors (PTs) and 163 paired metastatic lymph nodes (MLNs), and sections
of 56 cancer-adjacent normal epithelial blocks were used for CHIP evaluation by
immunohistochemistry. The clinical and prognostic significance of CHIP
expression was analyzed statistically.
RESULTS: The expression level of CHIP in ESCC MLNs was significantly higher than
that in PTs (P < 0.001). Patients with low MLNs' CHIP expression demonstrated
better overall survival than those with high CHIP expression (median, 44 vs.
17.9 months; P = 0.010). Multivariate analysis showed that the MLNs' CHIP
expression level was an independent prognostic factor in ESCC (relative risk,
2.157; P = 0.028).
CONCLUSIONS: High expression of CHIP in MLNs suggests poor prognosis for
patients with resected T3N1-3M0 ESCC. The result suggests that considering the
protein expression of metastatic tumors is important for prognostic prediction.
DOI: 10.1245/s10434-012-2733-4
PMID: 23429937 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23087371 | 1. Eukaryot Cell. 2012 Dec;11(12):1544-51. doi: 10.1128/EC.00228-12. Epub 2012
Oct 19.
Microsporidian infection in a free-living marine nematode.
Ardila-Garcia AM(1), Fast NM.
Author information:
(1)Department of Botany, University of British Columbia, Vancouver, British
Columbia, Canada.
Microsporidia are unicellular fungi that are obligate endoparasites. Although
nematodes are one of the most abundant and diverse animal groups, the only
confirmed report of microsporidian infection was that of the "nematode killer"
(Nematocida parisii). N. parisii was isolated from a wild Caenorhabditis sp. and
causes an acute and lethal intestinal infection in a lab strain of
Caenorhabditis elegans. We set out to characterize a microsporidian infection in
a wild nematode to determine whether the infection pattern of N. parisii in the
lab is typical of microsporidian infections in nematodes. We describe a novel
microsporidian species named Sporanauta perivermis (marine spore of roundworms)
and characterize its infection in its natural host, the free-living marine
nematode Odontophora rectangula. S. perivermis is not closely related to N.
parisii and differs strikingly in all aspects of infection. Examination by
transmission electron microscopy (TEM) revealed that the infection was localized
in the hypodermal and muscle tissues only and did not involve the intestines.
Fluorescent in situ hybridization (FISH) confirmed infection in the muscle and
hypodermis, and surprisingly, it also revealed that the parasite infects O.
rectangula eggs, suggesting a vertical mode of transmission. Our observations
highlight the importance of studying parasites in their natural hosts and
indicate that not all nematode-infecting microsporidia are "nematode killers";
instead, microsporidiosis can be more versatile and chronic in the wild.
DOI: 10.1128/EC.00228-12
PMCID: PMC3536275
PMID: 23087371 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1409666 | 1. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9564-8. doi:
10.1073/pnas.89.20.9564.
Characterization of the genes encoding phycoerythrin in the red alga Rhodella
violacea: evidence for a splitting of the rpeB gene by an intron.
Bernard C(1), Thomas JC, Mazel D, Mousseau A, Castets AM, Tandeau de Marsac N,
Dubacq JP.
Author information:
(1)Laboratoire des Biomembranes et Surfaces Cellulaires Végétales (Centre
National de la Recherche Scientifique, Unité de Recherches Associée 0311), Ecole
Normale Supérieure, Paris, France.
The phycobilisome of the eukaryotic unicellular red alga Rhodella violacea
presents in some respects an organization that is intermediate between those of
the homologous counterparts found in cyanobacteria (the putative chloroplast
progenitor) and more advanced, pluricellular red algae. This suggests
evolutionary relationships that we investigated at the genome level. The present
work describes the sequences of two rhodophytan phycobilisome genes, rpeA and
rpeB. These chloroplast genes encode the alpha and beta subunits of
phycoerythrin, the major component of the light-harvesting antennae and one of
the most abundant cellular proteins in these algae. The amino acid sequences
deduced from both rpeA and rpeB present strong homologies with those previously
reported for phycoerythrin subunits of cyanobacteria, rhodophyta, and
cryptomonads. The main difference with the corresponding cyanobacterial genes
was the unexpected occurrence of an intervening sequence that split rpeB into
two exons. This intervening sequence presents characteristics of group II
introns but lacks several structural domains. Transcriptional analyses showed
that the two rpe genes are cotranscribed and that the major RNA species detected
corresponds to a mature mRNA lacking the intron. As the phycobiliproteins form a
group of closely related polypeptides in cyanobacteria and rhodophyta, the
molecular events affecting the corresponding genes, such as the rpeB intron, may
be a clue to elucidate some aspects of the molecular processes involved in the
evolution of plastid genes.
DOI: 10.1073/pnas.89.20.9564
PMCID: PMC50172
PMID: 1409666 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6802826 | 1. J Biol Chem. 1982 Apr 25;257(8):4077-86.
Molecular architecture of a light-harvesting antenna. Isolation and
characterization of phycobilisome subassembly particles.
Yamanaka G, Lundell DJ, Glazer AN.
Synechococcus 6301 mutant, strain AN112, produces phycobilisomes containing two
major biliproteins, phycocyanin and allophycocyanin, and two major linker
polypeptides of 27 and 75 kilodaltons (27K and 75K). These phycobilisomes have a
molecular weight of approximately 2.5 X 10(6) and are the smallest of these
particles known to date. Sucrose density gradient centrifugation of AN112
phycobilisomes partially dissociated in 50 mM
N-[tris(hydroxymethyl)methyl]glycine, 5 mM CaCl2, 10% (w/v) glycerol, pH 7.8,
separated three distinct fractions: (1) free trimeric biliproteins, (2)
hexameric complexes of phycocyanin with 27K (11 S particles), and (3)
phycobilisome subassemblies equivalent in mass to approximately 25% of the
intact phycobilisome (18 S particles). The 18 S particles contained equimolar
amounts of phycocyanin and allophycocyanin, which represented approximately 30
and 50%, respectively, of the content of these biliproteins in the AN112
phycobilisome. The 18 S particles also contained 75% and 100%, respectively, of
27K and 75K polypeptides; i.e. 75K was present in a 2-fold higher amount than in
the intact phycobilisome. The absorption spectrum (lambda max 648 nm) of the 18
S particles was similar to that of allophycocyanin. Upon excitation at 580 nm,
these particles exhibited a fluorescence emission spectrum consisting of 680 and
660 nm components, identical with that of intact phycobilisomes. The circular
dichroism spectra of AN112 phycobilisomes and of the 18 S particles, in the
region between 650 and 700 nm, were also very similar. Allophycocyanin B, which
fluoresces at 680 nm, was found in fraction 1, and was totally absent from the
18 S particle. Thus, the long wavelength emission of the 18 S particle must have
arisen from another terminal energy acceptor. The most probable candidate is the
75K polypeptide, which has been shown to carry a bilin chromophore and emit near
680 nm (Lundell, D. J., Yamanaka, G., and Glazer, A. N. (1980) J. Cell Biol. 91,
315-319). The 27K polypeptide, present in both fractions 2 and 3, was a
component of different complexes in the two fractions. Fraction 2 displayed the
physical and spectroscopic properties characteristic of the phycocyanin-linker
complex, (alpha beta)6.27K. However, in the 18 S particle, 27K functioned in the
assembly and attachment of phycocyanin trimers to a core domain. Based on the
analysis of the components in fractions 1-3, a model is proposed which describes
the structure of the AN112 phycobilisome, with emphasis on the roles of the
linker polypeptides in the assembly of the core.
PMID: 6802826 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21964864 | 1. Int J Cancer. 2012 Aug 15;131(4):987-96. doi: 10.1002/ijc.26475. Epub 2011 Nov
10.
Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder
cancer-initiating cells.
Tatokoro M(1), Koga F, Yoshida S, Kawakami S, Fujii Y, Neckers L, Kihara K.
Author information:
(1)Department of Urology, Tokyo Medical and Dental University Graduate School,
Bunkyo-ku, Tokyo, Japan.
Comment in
J Urol. 2013 Apr;189(4):1596. doi: 10.1016/j.juro.2012.12.038.
For metastatic bladder cancer patients, systemic cisplatin (CDDP)-based
combination chemotherapy is the first-line choice of treatment. Although up to
70% of advanced bladder cancer patients initially show good tumor response to
this form of combination chemotherapy, over 90% of good responders relapse and
eventually die of the disease. According to the cancer stem cell theory, this
phenomenon is attributable to the re-growth of bladder cancer-initiating cells
(BCICs) that have survived chemotherapy. In this study, the authors have
isolated BCICs from cultured human bladder cancer cells to analyze their
sensitivity to CDDP and to investigate whether heat-shock protein 90 (Hsp90)
inhibitors potentiate the cytotoxicity of CDDP on BCICs. First, the authors have
confirmed that a CD44+ subpopulation of 5637 cells met the requirements to be
considered tumor-initiating cells. These BCICs were more resistant to CDDP and
exhibited more activity in the Akt and ERK oncogenic signaling pathways when
compared with their CD44- counterparts. The Hsp90 inhibitor
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which
simultaneously inactivated both Akt and ERK signaling at noncytocidal
concentrations, synergistically potentiated the cytotoxicity of CDDP against
BCICs by enhancing CDDP-induced apoptosis in vitro. The potentiating effect of
17-DMAG was more effective than a combination of the two inhibitors specific for
the Akt and ERK pathways. Finally, the authors have confirmed that, though human
BCIC xenografts exhibited resistance to a single administration of CDDP and the
Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-AAG
sensitized them to CDDP in a mouse model. These data encourage clinical trials
of Hsp90 inhibitors as they may improve therapeutic outcomes of CDDP-based
combination chemotherapy against advanced bladder cancer.
Copyright © 2011 UICC.
DOI: 10.1002/ijc.26475
PMCID: PMC7447157
PMID: 21964864 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17051209 | 1. Nature. 2006 Oct 19;443(7113):818-22. doi: 10.1038/nature05110.
Reconstructing the early evolution of Fungi using a six-gene phylogeny.
James TY(1), Kauff F, Schoch CL, Matheny PB, Hofstetter V, Cox CJ, Celio G,
Gueidan C, Fraker E, Miadlikowska J, Lumbsch HT, Rauhut A, Reeb V, Arnold AE,
Amtoft A, Stajich JE, Hosaka K, Sung GH, Johnson D, O'Rourke B, Crockett M,
Binder M, Curtis JM, Slot JC, Wang Z, Wilson AW, Schüssler A, Longcore JE,
O'Donnell K, Mozley-Standridge S, Porter D, Letcher PM, Powell MJ, Taylor JW,
White MM, Griffith GW, Davies DR, Humber RA, Morton JB, Sugiyama J, Rossman AY,
Rogers JD, Pfister DH, Hewitt D, Hansen K, Hambleton S, Shoemaker RA, Kohlmeyer
J, Volkmann-Kohlmeyer B, Spotts RA, Serdani M, Crous PW, Hughes KW, Matsuura K,
Langer E, Langer G, Untereiner WA, Lücking R, Büdel B, Geiser DM, Aptroot A,
Diederich P, Schmitt I, Schultz M, Yahr R, Hibbett DS, Lutzoni F, McLaughlin DJ,
Spatafora JW, Vilgalys R.
Author information:
(1)Department of Biology, Duke University, Durham, North Carolina 27708-0338,
USA. [email protected]
Comment in
Nature. 2006 Oct 19;443(7113):758-61. doi: 10.1038/443758a.
The ancestors of fungi are believed to be simple aquatic forms with flagellated
spores, similar to members of the extant phylum Chytridiomycota (chytrids).
Current classifications assume that chytrids form an early-diverging clade
within the kingdom Fungi and imply a single loss of the spore flagellum, leading
to the diversification of terrestrial fungi. Here we develop phylogenetic
hypotheses for Fungi using data from six gene regions and nearly 200 species.
Our results indicate that there may have been at least four independent losses
of the flagellum in the kingdom Fungi. These losses of swimming spores coincided
with the evolution of new mechanisms of spore dispersal, such as aerial
dispersal in mycelial groups and polar tube eversion in the microsporidia
(unicellular forms that lack mitochondria). The enigmatic microsporidia seem to
be derived from an endoparasitic chytrid ancestor similar to Rozella allomycis,
on the earliest diverging branch of the fungal phylogenetic tree.
DOI: 10.1038/nature05110
PMID: 17051209 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17572334 | 1. Mycol Res. 2007 May;111(Pt 5):509-47. doi: 10.1016/j.mycres.2007.03.004. Epub
2007 Mar 13.
A higher-level phylogenetic classification of the Fungi.
Hibbett DS(1), Binder M, Bischoff JF, Blackwell M, Cannon PF, Eriksson OE,
Huhndorf S, James T, Kirk PM, Lücking R, Thorsten Lumbsch H, Lutzoni F, Matheny
PB, McLaughlin DJ, Powell MJ, Redhead S, Schoch CL, Spatafora JW, Stalpers JA,
Vilgalys R, Aime MC, Aptroot A, Bauer R, Begerow D, Benny GL, Castlebury LA,
Crous PW, Dai YC, Gams W, Geiser DM, Griffith GW, Gueidan C, Hawksworth DL,
Hestmark G, Hosaka K, Humber RA, Hyde KD, Ironside JE, Kõljalg U, Kurtzman CP,
Larsson KH, Lichtwardt R, Longcore J, Miadlikowska J, Miller A, Moncalvo JM,
Mozley-Standridge S, Oberwinkler F, Parmasto E, Reeb V, Rogers JD, Roux C,
Ryvarden L, Sampaio JP, Schüssler A, Sugiyama J, Thorn RG, Tibell L, Untereiner
WA, Walker C, Wang Z, Weir A, Weiss M, White MM, Winka K, Yao YJ, Zhang N.
Author information:
(1)Biology Department, Clark University, Worcester, MA 01610, USA.
[email protected]
A comprehensive phylogenetic classification of the kingdom Fungi is proposed,
with reference to recent molecular phylogenetic analyses, and with input from
diverse members of the fungal taxonomic community. The classification includes
195 taxa, down to the level of order, of which 16 are described or validated
here: Dikarya subkingdom nov.; Chytridiomycota, Neocallimastigomycota phyla
nov.; Monoblepharidomycetes, Neocallimastigomycetes class. nov.;
Eurotiomycetidae, Lecanoromycetidae, Mycocaliciomycetidae subclass. nov.;
Acarosporales, Corticiales, Baeomycetales, Candelariales, Gloeophyllales,
Melanosporales, Trechisporales, Umbilicariales ords. nov. The clade containing
Ascomycota and Basidiomycota is classified as subkingdom Dikarya, reflecting the
putative synapomorphy of dikaryotic hyphae. The most dramatic shifts in the
classification relative to previous works concern the groups that have
traditionally been included in the Chytridiomycota and Zygomycota. The
Chytridiomycota is retained in a restricted sense, with Blastocladiomycota and
Neocallimastigomycota representing segregate phyla of flagellated Fungi. Taxa
traditionally placed in Zygomycota are distributed among Glomeromycota and
several subphyla incertae sedis, including Mucoromycotina,
Entomophthoromycotina, Kickxellomycotina, and Zoopagomycotina. Microsporidia are
included in the Fungi, but no further subdivision of the group is proposed.
Several genera of 'basal' Fungi of uncertain position are not placed in any
higher taxa, including Basidiobolus, Caulochytrium, Olpidium, and Rozella.
DOI: 10.1016/j.mycres.2007.03.004
PMID: 17572334 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23394616 | 1. Cancer Cell Int. 2013 Feb 8;13(1):11. doi: 10.1186/1475-2867-13-11.
Targeted inhibition of heat shock protein 90 disrupts multiple oncogenic
signaling pathways, thus inducing cell cycle arrest and programmed cell death in
human urinary bladder cancer cell lines.
Karkoulis PK(1), Stravopodis DJ, Konstantakou EG, Voutsinas GE.
Author information:
(1)Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of
Biosciences and Applications, National Center for Scientific Research (NCSR)
"Demokritos", Aghia Paraskevi, 15310, Athens, Greece.
[email protected].
BACKGROUND: Geldanamycin (GA) can be considered a relatively new component with
a promising mode of action against human malignancies. It specifically targets
heat shock protein 90 (Hsp90) and interferes with its function as a molecular
chaperone.
METHODS: In this study, we have investigated the effects of geldanamycin on the
regulation of Hsp90-dependent oncogenic signaling pathways directly implicated
in cell cycle progression, survival and motility of human urinary bladder cancer
cells. In order to assess the biological outcome of Hsp90 inhibition on RT4
(grade I) and T24 (grade III) human urinary bladder cancer cell lines, we
applied MTT assay, FACS analysis, Western blotting, semi-quantitative (sq)
RT-PCR, electrophoretic mobility shift assay (EMSA), immunofluorescence and
scratch-wound assay.
RESULTS: We have herein demonstrated that, upon geldanamycin treatment, bladder
cancer cells are prominently arrested in the G1 phase of cell cycle and
eventually undergo programmed cell death via combined activation of apoptosis
and autophagy. Furthermore, geldanamycin administration proved to induce
prominent downregulation of several Hsp90 protein clients and downstream
effectors, such as membrane receptors (IGF-IR and c-Met), protein kinases (Akt,
IKKα, IKKβ and Erk1/2) and transcription factors (FOXOs and NF-κΒ), therefore
resulting in the impairment of proliferative -oncogenic- signaling and reduction
of cell motility.
CONCLUSIONS: In toto, we have evinced the dose-dependent and cell line-specific
actions of geldanamycin on cell cycle progression, survival and motility of
human bladder cancer cells, due to downregulation of critical Hsp90 clients and
subsequent disruption of signaling -oncogenic- integrity.
DOI: 10.1186/1475-2867-13-11
PMCID: PMC3583703
PMID: 23394616 |
http://www.ncbi.nlm.nih.gov/pubmed/2163170 | 1. Zh Nevropatol Psikhiatr Im S S Korsakova. 1990;90(3):52-6.
[Proximal muscular dystrophy with contractures and malignant course: is it a
variant of Emery-Dreifuss disease?].
[Article in Russian]
Badalian Lo, Temin PA, Kalinin VA, Arkhipov BA, Zabadenko NN, Voloshina TG,
Lysov VL.
The authors relate a unique observation of the familial form of proximal
myodystrophy with early contractures and malignant course. The primary character
of muscular injury was confirmed on electromyography. The data of
electrocardiography and echocardiography attested to the presence in the
patients of the signs of cardiomyopathy. Since the disease was diagnosed in 3
brothers, the X-coupled recessive type of its inheritance is assumed. An opinion
is advanced that the described form is a clinical variety of Emery-Dreyfus
myodystrophy.
PMID: 2163170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20888031 | 1. Thromb Res. 2011 Jun;127(6):497-504. doi: 10.1016/j.thromres.2010.09.008. Epub
2010 Oct 2.
The mechanism of action of rivaroxaban--an oral, direct Factor Xa
inhibitor--compared with other anticoagulants.
Samama MM(1).
Author information:
(1)Hôtel-Dieu University Hospital, Paris, France. [email protected]
Although results of some phase III clinical trials of new oral anticoagulants
are now known, it is important to understand the mechanisms of their actions.
These new agents exert their anticoagulant effect via direct inhibition of a
single Factor within the coagulation cascade (such as Factor Xa or thrombin).
Rivaroxaban--the first oral, direct Factor Xa inhibitor--is a small-molecule
oxazolidinone derivative that binds directly and reversibly to Factor Xa via the
S1 and S4 pockets. Rivaroxaban competitively inhibits Factor Xa and is more than
10,000-fold more selective for Factor Xa than other related serine proteases,
and it does not require cofactors (such as antithrombin) to exert its
anticoagulant effect. Unlike indirect Factor Xa inhibitors, rivaroxaban inhibits
both free and clot-bound Factor Xa, as well as prothrombinase activity, thereby
prolonging clotting times. Dabigatran etexilate is a direct thrombin inhibitor
that inhibits both free and fibrin-bound thrombin. Although the mechanism of
action differs between the direct Factor Xa and direct thrombin inhibitors,
phase III studies of these new agents confirmed that both Factor Xa and thrombin
are viable anticoagulation targets.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.thromres.2010.09.008
PMID: 20888031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24005169 | 1. Otol Neurotol. 2013 Oct;34(8):1476-82. doi: 10.1097/MAO.0b013e3182a036c9.
Evaluation of the prognostic role of pSTAT3 expression in temporal bone squamous
cell carcinoma.
Marioni G(1), Nucci R, Marino F, Cappellesso R, Pillon M, Zanoletti E,
Giacomelli L, Franchella S, Billo P, Pareschi R, Martini A.
Author information:
(1)*Department of Neurosciences, Otolaryngology Section, Padova University
Hospital, Padova; †Otorhinolaryngology Division, Legnano Hospital, Legnano;
‡Department of Medicine DIMED, §Pediatric Onco-Hematology Unit, and ∥Department
of Neurosciences, Otosurgery Unit, Padova University Hospital, Padova; and
¶Anatomic Pathology Division, Legnano Hospital, Legnano, Italy.
OBJECTIVE: Temporal bone squamous cell carcinoma (SCC) accounts for less than
0.2% of all head and neck tumors. Although some progress has been made in
treating this aggressive tumor, the prognosis in advanced cases remains poor.
More effective therapeutic strategies need to be considered, including
receptor-mediated carcinoma-targeted therapy. Phosphorylated STAT3 (pSTAT3)
regulates many genes that are necessarily expressed in cancer initiation,
development, and progression, being involved in proliferation, anti-apoptosis,
invasion, angiogenesis, and immune surveillance evasion. The aim of the present
study was to preliminarily investigate the potential prognostic role of pSTAT3
expression in temporal bone SCC.
STUDY DESIGN: Retrospective clinicopathologic investigation.
SETTING: Tertiary referral centers.
PATIENTS: Twenty-five consecutively operated patients with primary temporal bone
SCC.
INTERVENTION: pSTAT3 immunohistochemical expression in primary temporal bone
SCCs was assessed with the aid of computer-based image analysis.
MAIN OUTCOME MEASURES: Conventional clinicopathologic parameters and pSTAT3
expression were correlated with SCC prognosis.
RESULTS: pT, stage, and surgical margin status were significantly related with
recurrence rate (p = 0.002, p = 0.01, and p = 0.047, respectively) and
disease-free survival (DFS) (p = 0.0049, p = 0.031, and p = 0.035,
respectively). pT classification was also related with disease-specific survival
(DSS) (p = 0.035). The SCC recurrence rate did not correlate with pSTAT3
expression. Statistical analyses ruled out any significant difference in DFS or
DSS when patients were stratified by pSTAT3 expression (>80.0% or ≤80.0%).
CONCLUSION: Despite our preliminary results, the role of pSTAT3 in temporal bone
SCC warrants further investigation in larger series because there is increasing
evidence in preclinical models to indicate that inhibiting STAT3 phosphorylation
can be a useful addition to different anticancer strategies.
DOI: 10.1097/MAO.0b013e3182a036c9
PMID: 24005169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21673069 | 1. Clin Cancer Res. 2011 Aug 1;17(15):5161-9. doi: 10.1158/1078-0432.CCR-10-2666.
Epub 2011 Jun 14.
EGF61 polymorphism predicts complete pathologic response to cetuximab-based
chemoradiation independent of KRAS status in locally advanced rectal cancer
patients.
Hu-Lieskovan S(1), Vallbohmer D, Zhang W, Yang D, Pohl A, Labonte MJ, Grimminger
PP, Hölscher AH, Semrau R, Arnold D, Dellas K, Debucquoy A, Haustermans K,
Machiels JP, Sempoux C, Rödel C, Bracko M, Velenik V, Lenz HJ.
Author information:
(1)Division of Medical Oncology, University of Southern California/Norris
Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90089,
USA.
BACKGROUND: Cetuximab has shown significant clinical activity in metastatic
colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not
been shown to improve tumor response in locally advanced rectal cancer patients
in recent phase I/II trials. We evaluated functional germline polymorphisms of
genes involved in epidermal growth factor receptor pathway, angiogenesis,
antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism,
for their potential role as molecular predictors for clinical outcome in locally
advanced rectal cancer patients treated with preoperative cetuximab-based
chemoradiation.
METHODS: 130 patients (74 men and 56 women) with locally advanced rectal cancer
(4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were
enrolled in phase I/II clinical trials treated with cetuximab-based
chemoradiation in European cancer centers were included. Genomic DNA was
extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was
done by using PCR-RFLP assays. Fisher's exact test was used to examine
associations between polymorphisms and complete pathologic response (pCR) that
was determined by a modified Dworak classification system (grade III vs. grade
IV: complete response).
RESULTS: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR
of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54)
in patients homozygous for the A/A allele (P < 0.001). In addition, this
association between EGF 61 G allele and pCR remained significant (P = 0.019) in
the 59 patients with wild-type KRAS.
CONCLUSION: This study suggested EGF A+61G polymorphism to be a predictive
marker for pCR, independent of KRAS mutation status, to cetuximab-based
neoadjuvant chemoradiation of patients with locally advanced rectal cancer.
©2011 AACR.
DOI: 10.1158/1078-0432.CCR-10-2666
PMCID: PMC3149732
PMID: 21673069 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20306699 | 1. Egypt J Immunol. 2008;15(2):161-7.
C-Phycocyanin inhibits cell proliferation and may induce apoptosis in human
HepG2 cells.
Basha OM(1), Hafez RA, El-Ayouty YM, Mahrous KF, Bareedy MH, Salama AM.
Author information:
(1)Department of Internal Medicine, Faculty of Medicine, Zagazig University,
Zagazig, Egypt.
C-Phycocyanin (C-Pc) is one of the major biliprotein pigments of unicellular
cyanbacterium of Spirulina platenesis, it has nutritional, medicinal, and
hepatoprotectant application. The growth and multiplication of human hepatoma
cell lines (HepG2) under the effect of different concentrations of C-PC (0.8,
1.75, 3.5 and 7.0 microg/ml) against untreated cells as control for 24h were
investigated. The results showed that the proliferating cells in presence of
C-PC reached 70, 51, 44, and 39%, respectively. The results revealed that the
greatest reduction in proliferation of cells was recorded at 7.0 microg/ml and
LC50 at 1.75 microg/ml of C-PC. In parallel, to the previous results
HCl-denatured MG-P revealed that in mass of cells there is a pattern of
apoptosis because the expanded cytoplasmic area (bluish-green) reduced and
appeared faintly red as C-PC concentration increased. Moreover, the cells lost
all the nuclear entities then, become fragmented and having no nuclear remnants.
The C-PC may be a new potential anti-cancer drug for therapy of human hepatoma
cells.
PMID: 20306699 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16569506 | 1. Protein Expr Purif. 2006 Sep;49(1):23-31. doi: 10.1016/j.pep.2006.02.001. Epub
2006 Feb 24.
Method for large-scale isolation and purification of R-phycoerythrin from red
alga Polysiphonia urceolata Grev.
Niu JF(1), Wang GC, Tseng CK.
Author information:
(1)Key Laboratory of Experimental Marine Biology, Institute of Oceanology,
Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071, China.
R-phycoerythrin was isolated and purified from a red alga, Polysiphonia
urceolata Grev, using Streamline column combined with ion-exchange
chromatography or hydroxyapatite chromatography. The purity of R-phycoerythrin
isolated by Streamline column was up to 1.66 and the yield of R-phycoerythrin
could be as high as 0.68 mg/g frozen P. urceolata. All the eluates from
Streamline column were divided into two equivalent parts, respectively. One part
was pumped into the ion-exchange column loaded with Q-Sepharose and the other
was applied to the adsorption column loaded with hydroxyapatite. The purities of
R-phycoerythrin purified using these two methods were both up to 3.26, more than
3.2 the commonly accepted criterion. The yield of purified R-phycoerythrin from
the ion-exchange chromatography was 0.40 mg/g frozen P. urceolata and that from
the hydroxyapatite chromatography could reach 0.34 mg/g frozen P. urceolata. The
purified protein had three absorption peaks at 498, 535, and 565 nm and
displayed a fluorescence maximum at 580 nm, which was consistent with the
typical spectrum of R-phycoerythrin. The purified R-PE was also identified with
electrophoresis. Only one single protein band appeared on native-PAGE with
silver staining. SDS-PAGE demonstrated the presence of one 20 kDa major subunit,
and one low intensity band corresponding to 33 kDa subunit. The results indicate
that using the expanded bed adsorption combined with ion-exchange chromatography
or hydroxyapatite chromatography, R-phycoerythrin can be purified from frozen P.
urceolata on large scale.
DOI: 10.1016/j.pep.2006.02.001
PMID: 16569506 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16061629 | 1. Cancer Res. 2005 Aug 1;65(15):6516-20. doi: 10.1158/0008-5472.CAN-05-0924.
Signal transducer and activator of transcription 3 (STAT3) regulates human
telomerase reverse transcriptase (hTERT) expression in human cancer and primary
cells.
Konnikova L(1), Simeone MC, Kruger MM, Kotecki M, Cochran BH.
Author information:
(1)Department of Physiology, Tufts University, Boston, Massachusetts 02111, USA.
Signal transducer and activator of transcription 3 (STAT3) is a transcription
factor that plays a critical role in cytokine and growth factor signaling and is
frequently activated in human tumors. Human telomerase reverse transcriptase
(hTERT) is also often overexpressed in tumor cells and mediates cellular
immortalization. Here we report that STAT3 directly regulates the expression of
hTERT in a variety of human cancer cells. Moreover, STAT3 activity is required
for the survival of many human tumors, and hTERT expression contributes to the
survival of STAT3-dependent tumor cells. In addition, we find that growth
factors and cytokines stimulate hTERT expression in primary human cells in a
STAT3-dependent manner. Thus, STAT3 is a key regulator of hTERT expression in
both normal and tumor cells.
DOI: 10.1158/0008-5472.CAN-05-0924
PMID: 16061629 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10332042 | 1. Hum Mol Genet. 1999 Jun;8(6):1091-8. doi: 10.1093/hmg/8.6.1091.
Defective intracellular transport of CLN3 is the molecular basis of Batten
disease (JNCL).
Järvelä I(1), Lehtovirta M, Tikkanen R, Kyttälä A, Jalanko A.
Author information:
(1)National Public Health Institute, Laboratory of Human Molecular Genetics,
Helsinki, Finland. [email protected]
Erratum in
Hum Mol Genet 1999 Aug;8(8):1585.
Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most
common progressive encephalopathy of childhood, is caused by mutations in a
novel lysosomal membrane protein (CLN3) with unknown function. In this study, we
have confirmed the lysosomal localization of the CLN3 protein by immunoelectron
microscopy by co-localizing it with soluble and membrane-associated lysosomal
proteins. We have analysed the intracellular processing and localization of two
mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the
classical JNCL, and E295K [corrected], which is a rare missense mutation
associated with an atypical form of JNCL. Pulse-chase labelling and
immunoprecipitation of the two mutant proteins in COS-1-cells indicated that
461-677del is synthesized as an approximately 24 kDa truncated polypeptide,
whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3
polypeptide. Transient expression of the two mutants in BHK cells showed that
461-677del is retained in the endoplasmic reticulum, whereas E295K [corrected]
was capable of reaching the lysosomal compartment. The CLN3 polypeptides were
expressed further in mouse primary neurons where the wild-type CLN3 protein was
localized both in the cell soma and in neuronal extensions, whereas the
461-677del mutant was arrested in the cell soma. Interestingly, co-localization
of the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle
marker indicates that the CLN3 protein might participate in synaptic vesicle
transport/transmission. The data presented here provide clear evidence for a
cellular distinction between classical and atypical forms of Batten disease both
in neural and non-neural cells.
DOI: 10.1093/hmg/8.6.1091
PMID: 10332042 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10666703 | 1. Mol Biol Evol. 2000 Jan;17(1):23-31. doi:
10.1093/oxfordjournals.molbev.a026235.
Evidence from beta-tubulin phylogeny that microsporidia evolved from within the
fungi.
Keeling PJ(1), Luker MA, Palmer JD.
Author information:
(1)Department of Biology, Indiana University at Bloomington, USA.
[email protected]
Microsporidia are obligate intracellular parasites that were thought to be an
ancient eukaryotic lineage based on molecular phylogenies using ribosomal RNA
and translation elongation factors. However, this ancient origin of
microsporidia has been contested recently, as several other molecular
phylogenies suggest that microsporidia are closely related to fungi. Most of the
protein trees that place microsporidia with fungi are not well sampled, however,
and it is impossible to resolve whether microsporidia evolved from a fungus or
from a protistan relative of fungi. We have sequenced beta-tubulins from 3
microsporidia, 4 chytrid fungi, and 12 zygomycete fungi, expanding the
representation of beta-tubulin to include all four fungal divisions and a wide
diversity of microsporidia. In phylogenetic trees including these new sequences,
the overall topology of the fungal beta-tubulins generally matched the expected
relationships among the four fungal divisions, although the zygomycetes were
polyphyletic in some analyses. The microsporidia consistently fell within this
fungal diversification, and not as a sister group to fungi. Overall,
beta-tubulin phylogeny suggests that microsporidia evolved from a fungus
sometime after the divergence of chytrids. We also found that chytrid alpha- and
beta-tubulins are much less divergent than are tubulins from other fungi or
microsporidia. In trees in which the only fungal representatives were the
chytrids, microsporidia still branched with fungi (i.e., with chytrids),
suggesting that the affiliation between microsporidian and fungal tubulins is
not an artifact of long-branch attraction.
DOI: 10.1093/oxfordjournals.molbev.a026235
PMID: 10666703 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21162130 | 1. J Neurosci Res. 2011 Feb;89(2):231-47. doi: 10.1002/jnr.22537. Epub 2010 Dec
8.
Characterization of kinases involved in the phosphorylation of aggregated
α-synuclein.
Waxman EA(1), Giasson BI.
Author information:
(1)Department of Pharmacology, University of Pennsylvania, Philadelphia,
Pennsylvania, USA.
α-Synuclein (α-syn) is the major component of pathological inclusions
characteristic of several neurodegenerative disorders, such as Parkinson's
disease. The major posttranslational modification of α-syn is phosphorylation at
S129, and previous studies estimate that approximately 90% of α-syn in
proteinaceous, pathological inclusions is phosphorylated at this site. α-Syn can
be phosphorylated by polo-like kinases (PLKs) 1-3 and casein kinases (CK) 1 and
2; however, the kinases associated with the hyperphosphorylation of aggregated
α-syn are still under debate. Using a high-efficiency cellular model of α-syn
aggregate formation, we found that selective inhibitors for CK2 and PLKs each
partially inhibited S129 phosphorylation of soluble (nonaggregated) α-syn, but
only PLK inhibitors modestly attenuated the phosphorylation of aggregated α-syn.
In addition, none of the kinase inhibitors used had a substantial effect on the
propensity of α-syn to aggregate. Overexpression of all PLKs promoted robust
phosphorylation of soluble α-syn, but none altered the propensity of α-syn to
aggregate. Overexpression of only PLK2 increased phosphorylation of aggregated
α-syn at S129, which likely is due to increased phosphorylation of soluble
α-syn, which then was incorporated into aggregates. Overexpression of PLK1 and
treatment with BI2536 resulted in a significant reduction of phosphorylated,
aggregated α-syn protein, beyond that of BI2536 treatment alone. These studies
suggest that phosphorylation of α-syn is independent of α-syn aggregate
formation, that PLK1 is involved in the phosphorylation of aggregated α-syn at
S129 in this system, and that mechanisms resulting in hyperphosphorylation of
aggregated α-syn appear to be independent of those responsible for the
phosphorylation of soluble α-syn.
Copyright © 2010 Wiley-Liss, Inc.
DOI: 10.1002/jnr.22537
PMCID: PMC4484797
PMID: 21162130 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8344905 | 1. J Biol Chem. 1993 Aug 5;268(22):16208-15.
The gamma subunit of R-phycoerythrin and its possible mode of transport into the
plastid of red algae.
Apt KE(1), Hoffman NE, Grossman AR.
Author information:
(1)Department of Plant Biology, Carnegie Institution of Washington, Stanford,
California 94305.
R-phycoerythrin is the major light-harvesting pigment protein of most red algal
phycobilisomes. It is composed of three pigmented polypeptide subunits, the
alpha, beta, and gamma. While alpha and beta phycoerythrin subunits are each
unique in the red alga Aglaothamnion neglectum, there are two different gamma
subunits with distinct molecular masses. Both gamma subunits are pigmented by
virtue of covalently attached linear tetrapyrroles. The amino acid sequence of
one of the gamma subunits, as deduced from the nucleotide sequence of a cDNA
clone, has no significant similarity to any known sequence in the data bases.
This result is surprising, since the gamma subunit of phycoerythrin is thought
to have a function that is similar to cyanobacterial linker polypeptides. The A.
neglectum gamma subunit is synthesized as a 36-kDa precursor protein that is
processed at the amino terminus to yield a 33-kDa mature protein. The
amino-terminal extension was able to direct the pea small subunit of Rubisco
into isolated pea chloroplasts. This result suggests that red algae transport
proteins into the plastid by a mechanism similar to that of higher plants. There
are significant changes in levels of mRNA encoding the gamma 33 subunit when A.
neglectum is grown under different conditions of illumination and in
nitrogen-deficient medium. These changes parallel those previously observed for
transcripts encoding the alpha and beta phycoerythrin subunits. Hence, there may
be coordinated expression of nuclear and plastid-encoded phycoerythrin subunit
genes.
PMID: 8344905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16597327 | 1. BMC Bioinformatics. 2006 Apr 5;7:189. doi: 10.1186/1471-2105-7-189.
Algorithms for incorporating prior topological information in HMMs: application
to transmembrane proteins.
Bagos PG(1), Liakopoulos TD, Hamodrakas SJ.
Author information:
(1)Department of Cell Biology and Biophysics, Faculty of Biology, University of
Athens, Athens 157 01, Greece. [email protected]
BACKGROUND: Hidden Markov Models (HMMs) have been extensively used in
computational molecular biology, for modelling protein and nucleic acid
sequences. In many applications, such as transmembrane protein topology
prediction, the incorporation of limited amount of information regarding the
topology, arising from biochemical experiments, has been proved a very useful
strategy that increased remarkably the performance of even the top-scoring
methods. However, no clear and formal explanation of the algorithms that retains
the probabilistic interpretation of the models has been presented so far in the
literature.
RESULTS: We present here, a simple method that allows incorporation of prior
topological information concerning the sequences at hand, while at the same time
the HMMs retain their full probabilistic interpretation in terms of conditional
probabilities. We present modifications to the standard Forward and Backward
algorithms of HMMs and we also show explicitly, how reliable predictions may
arise by these modifications, using all the algorithms currently available for
decoding HMMs. A similar procedure may be used in the training procedure, aiming
at optimizing the labels of the HMM's classes, especially in cases such as
transmembrane proteins where the labels of the membrane-spanning segments are
inherently misplaced. We present an application of this approach developing a
method to predict the transmembrane regions of alpha-helical membrane proteins,
trained on crystallographically solved data. We show that this method compares
well against already established algorithms presented in the literature, and it
is extremely useful in practical applications.
CONCLUSION: The algorithms presented here, are easily implemented in any kind of
a Hidden Markov Model, whereas the prediction method (HMM-TM) is freely
available for academic users at http://bioinformatics.biol.uoa.gr/HMM-TM,
offering the most advanced decoding options currently available.
DOI: 10.1186/1471-2105-7-189
PMCID: PMC1523218
PMID: 16597327 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18976912 | 1. Curr Biol. 2008 Nov 11;18(21):1675-9. doi: 10.1016/j.cub.2008.09.030. Epub
2008 Oct 30.
Microsporidia evolved from ancestral sexual fungi.
Lee SC(1), Corradi N, Byrnes EJ 3rd, Torres-Martinez S, Dietrich FS, Keeling PJ,
Heitman J.
Author information:
(1)Department of Molecular Genetics and Microbiology, Duke University Medical
Center, Durham, NC 27710, USA.
Microsporidia are obligate, intracellular eukaryotic pathogens that infect
animal cells, including humans [1]. Previous studies suggested microsporidia
share a common ancestor with fungi [2-7]. However, the exact nature of this
phylogenetic relationship is unclear because of unusual features of
microsporidial genomes, which are compact with fewer and highly divergent genes
[8]. As a consequence, it is unclear whether microsporidia evolved from a
specific fungal lineage, or whether microsporidia are a sister group to all
fungi. Here, we present evidence addressing this controversial question that is
independent of sequence-based phylogenetic reconstruction, but rather based on
genome structure. In the zygomycete basal fungal lineage, the sex locus is a
syntenic gene cluster governing sexual reproduction in which a high mobility
group (HMG) transcription-factor gene is flanked by triose-phosphate transporter
(TPT) and RNA helicase genes [9]. Strikingly, microsporidian genomes harbor a
sex-related locus with the same genes in the same order. Genome-wide synteny
analysis reveals multiple other loci conserved between microsporidia and
zygomycetes to the exclusion of all other fungal lineages with sequenced
genomes. These findings support the hypothesis that microsporidia are true fungi
that descended from a zygomycete ancestor and suggest microsporidia may have an
extant sexual cycle.
DOI: 10.1016/j.cub.2008.09.030
PMCID: PMC2654606
PMID: 18976912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11591467 | 1. Gene. 2001 Oct 3;276(1-2):15-24. doi: 10.1016/s0378-1119(01)00667-9.
Compositional heterogeneity within and among isochores in mammalian genomes. I.
CsCl and sequence analyses.
Clay O(1), Carels N, Douady C, Macaya G, Bernardi G.
Author information:
(1)Laboratory of Molecular Evolution, Stazione Zoologica Anton Dohrn, Villa
Comunale, 80121, Naples, Italy.
GC level distributions of a species' nuclear genome, or of its compositional
fractions, encode key information on structural and functional properties of the
genome and on its evolution. They can be calculated either from absorbance
profiles of the DNA in CsCl density gradients at sedimentation equilibrium, or
by scanning long contigs of largely sequenced genomes. In the present study, we
address the quantitative characterization of the compositional heterogeneity of
genomes, as measured by the GC distributions of fixed-length fragments. Special
attention is given to mammalian genomes, since their compartmentalization into
isochores implies two levels of heterogeneity, intra-isochore (local) and
inter-isochore (global). This partitioning is a natural one, since large-scale
compositional properties vary much more among isochores than within them.
Intra-isochore GC distributions become roughly Gaussian for long fragments, and
their standard deviations decrease only slowly with increasing fragment length,
unlike random sequences. This effect can be explained by 'long-range'
correlations, often overlooked, that are present along isochores.
DOI: 10.1016/s0378-1119(01)00667-9
PMID: 11591467 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22934101 | 1. Front Genet. 2012 Jun 1;3:98. doi: 10.3389/fgene.2012.00098. eCollection 2012.
Large homogeneous genome regions (isochores) in soybean [glycine max (L.) merr].
Woody JL(1), Beavis W, Shoemaker RC.
Author information:
(1)Interdepartmental Genetics Program, Iowa State University Ames, IA, USA.
The landscape of plant genomes, while slowly being characterized and defined, is
still composed primarily of regions of undefined function. Many eukaryotic
genomes contain isochore regions, mosaics of homogeneous GC content that can
abruptly change from one neighboring isochore to the next. Isochores are broken
into families that are characterized by their GC levels. We identified 4,339
compositionally distinct domains and 331 of these were identified as long
homogeneous genome regions (LHGRs). We assigned these to four families based on
finite mixture models of GC content. We then characterized each family with
respect to exon length, gene content, and transposable elements. The LHGR
pattern of soybeans is unique in that while the majority of the genes within
LHGRs are found within a single LHGR family with a narrow GC range (Family B),
that family is not the highest in GC content as seen in vertebrates and
invertebrates. Instead Family B has a mean GC content of 35%. The range of GC
content for all LHGRs is 16-59% GC which is a larger range than what is typical
of vertebrates. This is the first study in which LHGRs have been identified in
soybeans and the functions of the genes within the LHGRs have been analyzed.
DOI: 10.3389/fgene.2012.00098
PMCID: PMC3365285
PMID: 22934101 |
http://www.ncbi.nlm.nih.gov/pubmed/23466964 | 1. Hosp Pract (1995). 2013 Feb;41(1):19-25. doi: 10.3810/hp.2013.02.1009.
Inhibitory effect of apixaban compared with rivaroxaban and dabigatran on
thrombin generation assay.
Wong PC(1), White A, Luettgen J.
Author information:
(1)Bristol-Myers Squibb Company, Princeton, NJ, USA. [email protected]
The effect of the oral direct activated factor X (factor Xa) inhibitor apixaban
on tissue factor-induced thrombin generation in human plasma was investigated in
vitro using the calibrated automated thrombogram (CAT) method and compared with
the oral direct factor Xa inhibitor rivaroxaban and the direct thrombin
inhibitor dabigatran. Pooled citrated, anticoagulated, platelet-poor human
plasma was spiked with apixaban, rivaroxaban, or dabigatran at concentrations of
0.01 to 10 μM. The inhibitory potencies of the compounds were quantified by 5
CAT parameters: the control thrombin lag time (LT) and time to thrombin peak
(TTP) for the doubling of inhibitor concentration (IC2x); and the control
endogenous thrombin potential (ETP), thrombin peak, and maximum rate of thrombin
generation (Vmax) for the inhibitor concentration, which inhibited 50% (IC50).
The inhibitors modified CAT concentration dependently. Their inhibitory
potencies, expressed as IC2x LT, IC2x TTP, IC50 ETP, IC50 peak thrombin, and
IC50 Vmax, were as follows: 0.10 ± 0.01, 0.19 ± 0.02, 0.65 ± 0.11, 0.089 ±
0.019, and 0.049 ± 0.007 μM for apixaban; 0.049 ± 0.007, 0.070 ± 0.009, 0.43 ±
0.07, 0.048 ± 0.008, and 0.022 ± 0.005 μM for rivaroxaban; and 0.063 ± 0.019,
0.18 ± 0.06, 0.50 ± 0.08, 0.55 ± 0.06, and 0.57 ± 0.27 μM for dabigatran. In
summary, apixaban, rivaroxaban, and dabigatran have similar potencies in the
prolongation of LT and TTP. The CAT parameters that are related to the rate of
thrombin generation during the propagation phase (ie, peak thrombin and Vmax)
are more sensitive to activities of apixaban and rivaroxaban than dabigatran.
The ETP is the least sensitive parameter for measuring the activities of these
inhibitors. Recombinant activated factor VII at 5 and 50 μg/mL reversed the
anticoagulant effects of apixaban more at 0.2 μM than at 2 μM. Our study
suggests that the CAT method is a sensitive assay to monitor the pharmacodynamic
and pharmacokinetic properties of apixaban, rivaroxaban, and dabigatran, and may
provide insight into the mechanism of action of these inhibitors. Recombinant
activated factor VII may have some potential to reverse the anticoagulant
effects of apixaban in vitro.
DOI: 10.3810/hp.2013.02.1009
PMID: 23466964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22503551 | 1. Int J Food Microbiol. 2012 May 15;156(2):152-60. doi:
10.1016/j.ijfoodmicro.2012.03.017. Epub 2012 Mar 27.
Evaluation of some physical and chemical treatments for inactivating
microsporidian spores isolated from fish.
Leiro JM(1), Piazzon C, Domínguez B, Mallo N, Lamas J.
Author information:
(1)Departamento de Microbiología y Parasitología, Laboratorio de Parasitología;
Instituto de Investigación y Análisis Alimentarios, Universidad de Santiago de
Compostela, 15782, Santiago de Compostela, Spain. [email protected]
Microsporidia are a large diverse group of intracellular parasites now
considered as fungi. They are particularly prevalent in fish and are recognized
as important opportunistic parasites in humans. Although the mode of
transmission of microsporidia has not been fully clarified, the consumption and
manipulation of infected fish may be a risk factor for humans. Comparative
analysis of rDNA sequence revealed that the microsporidians used in the present
study had 99-100% identity with anglerfish microsporidians of the genus Spraguea
and very low identity with microsporidians that infect humans. Microsporidian
spores were exposed to different physical and chemical treatments: freezing at
-20°C for 24-78 h, heating at 60°C for 5-15 min, microwaving at 700 W, 2.45 GHz
for 15-60s, and treatment with ethanol at concentrations of between 1 and 70%
for 15 min. The viability of the spores after each treatment was evaluated by
two methods: a) haemocytometer counts, measuring the extrusion of the polar
filament in control and treated spores, and b) a fluorometric method, testing
the membrane integrity by propidium iodide exclusion. The results of both
methods were concordant. Spores were inactivated by freezing at -20°C for more
than 48 h, by heating to 60°C for 10 min and by microwaving at 750 W, for 20s.
Exposure to 70% ethanol for 15 min also inactivated microsporidian spores. The
results suggest that both freezing and heating are effective treatments for
destroying microsporidian spores in European white anglerfish, and that 70%
ethanol could be used by fish processors to disinfect their hands and the
utensils used in processing fish. The fluorometric method can be used as an
alternative to haemocytometer counts in disinfection studies aimed at
establishing strategies for inactivating and reducing the viability and the
potential infectivity of microsporidians present in fish or in the environment.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ijfoodmicro.2012.03.017
PMID: 22503551 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19812766 | 1. Bioinform Biol Insights. 2008 Jan 31;2:67-74. doi: 10.4137/bbi.s358.
HMM_RA: an improved method for alpha-helical transmembrane protein topology
prediction.
Hu J(1), Yan C.
Author information:
(1)Department of Computer Science, Utah State University, Logan, UT 84322 USA.
alpha-helical transmembrane (TM) proteins play important and diverse functional
roles in cells. The ability to predict the topology of these proteins is
important for identifying functional sites and inferring function of membrane
proteins. This paper presents a Hidden Markov Model (referred to as HMM_RA) that
can predict the topology of alpha-helical transmembrane proteins with improved
performance. HMM_RA adopts the same structure as the HMMTOP method, which has
five modules: inside loop, inside helix tail, membrane helix, outside helix tail
and outside loop. Each module consists of one or multiple states. HMM_RA allows
using reduced alphabets to encode protein sequences. Thus, each state of HMM_RA
is associated with n emission probabilities, where n is the size of the reduced
alphabet set. Direct comparisons using two standard data sets show that HMM_RA
consistently outperforms HMMTOP and TMHMM in topology prediction. Specifically,
on a high-quality data set of 83 proteins, HMM_RA outperforms HMMTOP by up to
7.6% in topology accuracy and 6.4% in alpha-helices location accuracy. On the
same data set, HMM_RA outperforms TMHMM by up to 6.4% in topology accuracy and
2.9% in location accuracy. Comparison also shows that HMM_RA achieves comparable
performance as Phobius, a recently published method.
DOI: 10.4137/bbi.s358
PMCID: PMC2735969
PMID: 19812766 |
http://www.ncbi.nlm.nih.gov/pubmed/9254920 | 1. Mol Biol Evol. 1997 Aug;14(8):823-8. doi:
10.1093/oxfordjournals.molbev.a025823.
Evolution of isochores in rodents.
Robinson M(1), Gautier C, Mouchiroud D.
Author information:
(1)Laboratoire de Biométrie, Génétique et Biologie des Populations, Université
Claude Bernard, Lyon, I UMR-CNRS 5558, Villeurbanne, France.
[email protected]
The most deviant isochore pattern within mammals was found in rat and mouse;
most other mammals possess a different kind of isochore organization called the
"general pattern." However, isochore patterns remain largely unknown in rodents
other than mouse and rat. To investigate the taxonomic distribution of isochore
patterns in rodents, we sequenced the nuclear gene LCAT (lecithin:cholesterol
acyltransferase) from 17 rodents species (bringing the total of LCAT sequences
in rodent to 19) and compared their GC contents at third codon positions and in
introns. We also analyzed an extensive sequence database from rodents other than
rat and mouse. All murid LCAT sequences are much poorer in GC than all nonrodent
LCAT sequences, and the hamster sequence database shows exactly the same
isochore pattern as rat and mouse. Thus, all murids share the same special
isochore pattern--GC homogenization. LCAT sequences are GC-poor in
hystricomorphs too, but the guinea pig sequence database indicates that large
changes in GC content occur without an overall modification of the isochore
pattern. This novel mode of isochore evolution is called GC reordering. LCAT
sequences also show that the evolution of isochores in sciurids and glirids is
nonconservative in comparison with that in nonrodents. Thus, at least two novel
patterns of isochore evolution were found. No rodent investigated to date shared
the general mammalian pattern.
DOI: 10.1093/oxfordjournals.molbev.a025823
PMID: 9254920 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11590105 | 1. Bioinformatics. 2001 Sep;17(9):849-50. doi: 10.1093/bioinformatics/17.9.849.
The HMMTOP transmembrane topology prediction server.
Tusnády GE(1), Simon I.
Author information:
(1)Institute of Enzymology, BRC, Hungarian Academy of Sciences, H-1518 Budapest,
PO Box 7, Hungary. [email protected]
The HMMTOP transmembrane topology prediction server predicts both the
localization of helical transmembrane segments and the topology of transmembrane
proteins. Recently, several improvements have been introduced to the original
method. Now, the user is allowed to submit additional information about segment
localization to enhance the prediction power. This option improves the
prediction accuracy as well as helps the interpretation of experimental results,
i.e. in epitope insertion experiments.
AVAILABILITY: HMMTOP 2.0 is freely available to non-commercial users at
http://www.enzim.hu/hmmtop. Source code is also available upon request to
academic users.
DOI: 10.1093/bioinformatics/17.9.849
PMID: 11590105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9809012 | 1. Biol Rev Camb Philos Soc. 1998 Aug;73(3):203-66. doi:
10.1017/s0006323198005167.
A revised six-kingdom system of life.
Cavalier-Smith T(1).
Author information:
(1)Canadian Institute for Advanced Research, Department of Botany, University of
British Columbia, Vancouver, Canada.
A revised six-kingdom system of life is presented, down to the level of
infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and
eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi,
Plantae and Chromista. Intermediate high level categories (superkingdom,
subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are
extensively used to avoid splitting organisms into an excessive number of
kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms,
Protozoa and Animalia, are subject to the International Code of Zoological
Nomenclature, the kingdom Bacteria to the International Code of Bacteriological
Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to
the International Code of Botanical Nomenclature. Circumscriptions of the
kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The
kingdom Fungi is expanded by adding Microsporidia, because of protein sequence
evidence that these amitochondrial intracellular parasites are related to
conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20
classes; fungal classification at the rank of subclass and above is
comprehensively revised. The kingdoms Protozoa and Animalia are modified in the
light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not
Protozoa, and that mesozoans are related to bilaterian animals. Animalia are
divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa,
Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other
phyla). Several new higher level groupings are made in the animal kingdom
including three new phyla: Acanthognatha (rotifers, acanthocephalans,
gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and
Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are
recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are
treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not
as a separate kingdom. The recently revised phylum Rhizopoda is modified further
by adding more flagellates and removing some 'rhizopods' and is therefore
renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa
and Archamoebae (both now infraphyla) as a new subphylum Conosa within the
phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the
traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the
(formerly microsporidian) metchnikovellids are now both placed within the phylum
Sporozoa. These changes make a total of only 13 currently recognized protozoan
phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is
modified in circumscription by adding the Discicristata, a new infrakingdom
comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in
relation to the principles of megasystematics, here defined as systematics that
concentrates on the higher levels of classes, phyla, and kingdoms. These
principles also make it desirable to rank Archaebacteria as an infrakingdom of
the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with
the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising
all bacteria bounded by a single membrane. The bacterial subkingdom
Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into
two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only
phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides
in the outer leaflet of the outer membrane and phospholipids in its inner
leaflet. (ABSTRACT TRUNCATED)
DOI: 10.1017/s0006323198005167
PMID: 9809012 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22627188 | 1. Semin Cancer Biol. 2012 Oct;22(5-6):455-61. doi:
10.1016/j.semcancer.2012.05.004. Epub 2012 May 22.
TGF-β-induced epithelial-mesenchymal transition: a link between cancer and
inflammation.
Fuxe J(1), Karlsson MC.
Author information:
(1)Department of Medical Biochemistry and Biophysics, Division of Vascular
Biology, Karolinska Institute, SE-17177 Stockholm, Sweden. [email protected]
Metastatic spread of tumor cells to vital organs is the major cause of death in
cancer. Accumulating data support an important role of infiltrating immune cells
in promoting carcinoma progression into metastatic disease. Tumor-infiltrating
immune cells produce and secrete cytokines, growth factors and proteases that
re-activate latent developmental processes including epithelial-mesenchymal
transition (EMT). EMT provides tumor cells with invasive, migratory and stem
cell properties allowing them to disseminate and propagate at distant sites.
Induction of EMT requires two criteria to be fulfilled: (i) cells are competent
to undergo EMT (ii) an EMT-permissive microenvironment exists. The cytokine
TGF-β, which is expressed by tumor-infiltrating immune cells, stands out as a
master regulator of the pro-invasive tumor microenvironment. TGF-β cooperates
with stem cell pathways, such as Wnt and Ras signaling, to induce EMT. In
addition, TGF-β contributes to an EMT-permissive microenvironment by switching
the phenotypes of tumor-infiltrating immune cells, which thereby mount
pro-invasive and pro-metastatic immune responses. In this review, we discuss the
role of TGF-β-induced EMT as a link between cancer and inflammation in the
context of questions, which from our point of view are key to answer in order to
understand the functionality of EMT in tumors.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.semcancer.2012.05.004
PMID: 22627188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16024809 | 1. Mol Cell Biol. 2005 Aug;25(15):6760-71. doi: 10.1128/MCB.25.15.6760-6771.2005.
Direct activation of genes involved in intracellular iron use by the yeast
iron-responsive transcription factor Aft2 without its paralog Aft1.
Courel M(1), Lallet S, Camadro JM, Blaiseau PL.
Author information:
(1)Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département
de Biologie des Génomes, Institut Jacques-Monod, UMR 7592 CNRS-Universités Paris
6 and 7, 2 Place Jussieu, F-75251 Paris cedex 05, France.
The yeast Saccharomyces cerevisiae contains a pair of paralogous iron-responsive
transcription activators, Aft1 and Aft2. Aft1 activates the cell surface iron
uptake systems in iron depletion, while the role of Aft2 remains poorly
understood. This study compares the functions of Aft1 and Aft2 in regulating the
transcription of genes involved in iron homeostasis, with reference to the
presence/absence of the paralog. Cluster analysis of DNA microarray data
identified the classes of genes regulated by Aft1 or Aft2, or both. Aft2
activates the transcription of genes involved in intracellular iron use in the
absence of Aft1. Northern blot analyses, combined with chromatin
immunoprecipitation experiments on selected genes from each class, demonstrated
that Aft2 directly activates the genes SMF3 and MRS4 involved in mitochondrial
and vacuolar iron homeostasis, while Aft1 does not. Computer analysis found
different cis-regulatory elements for Aft1 and Aft2, and transcription analysis
using variants of the FET3 promoter indicated that Aft1 is more specific for the
canonical iron-responsive element TGCACCC than is Aft2. Finally, the absence of
either Aft1 or Aft2 showed an iron-dependent increase in the amount of the
remaining paralog. This may provide additional control of cellular iron
homeostasis.
DOI: 10.1128/MCB.25.15.6760-6771.2005
PMCID: PMC1190354
PMID: 16024809 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20439772 | 1. Genetics. 2010 Jul;185(3):1111-28. doi: 10.1534/genetics.110.117531. Epub 2010
May 3.
Functional genomics analysis of the Saccharomyces cerevisiae iron responsive
transcription factor Aft1 reveals iron-independent functions.
Berthelet S(1), Usher J, Shulist K, Hamza A, Maltez N, Johnston A, Fong Y,
Harris LJ, Baetz K.
Author information:
(1)Eastern Cereal and Oilseed Research Centre, Agriculture and Agri-Food Canada,
Ottawa, Ontario K1A 0C6, Canada.
The Saccharomyces cerevisiae transcription factor Aft1 is activated in
iron-deficient cells to induce the expression of iron regulon genes, which
coordinate the increase of iron uptake and remodel cellular metabolism to
survive low-iron conditions. In addition, Aft1 has been implicated in numerous
cellular processes including cell-cycle progression and chromosome stability;
however, it is unclear if all cellular effects of Aft1 are mediated through iron
homeostasis. To further investigate the cellular processes affected by Aft1, we
identified >70 deletion mutants that are sensitive to perturbations in AFT1
levels using genome-wide synthetic lethal and synthetic dosage lethal screens.
Our genetic network reveals that Aft1 affects a diverse range of cellular
processes, including the RIM101 pH pathway, cell-wall stability, DNA damage,
protein transport, chromosome stability, and mitochondrial function.
Surprisingly, only a subset of mutants identified are sensitive to extracellular
iron fluctuations or display genetic interactions with mutants of iron regulon
genes AFT2 or FET3. We demonstrate that Aft1 works in parallel with the RIM101
pH pathway and the role of Aft1 in DNA damage repair is mediated by iron. In
contrast, through both directed studies and microarray transcriptional
profiling, we show that the role of Aft1 in chromosome maintenance and benomyl
resistance is independent of its iron regulatory role, potentially through a
nontranscriptional mechanism.
DOI: 10.1534/genetics.110.117531
PMCID: PMC2900968
PMID: 20439772 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18031713 | 1. Biochem Pharmacol. 2008 Feb 15;75(4):900-6. doi: 10.1016/j.bcp.2007.10.011.
Epub 2007 Oct 16.
Reduced expression of thyroid hormone receptors and beta-adrenergic receptors in
human failing cardiomyocytes.
Modesti PA(1), Marchetta M, Gamberi T, Lucchese G, Maccherini M, Chiavarelli M,
Modesti A.
Author information:
(1)Department of Critical Care Medicine, University of Florence, Viale Morgagni
85, 50134 Florence, Italy. [email protected]
An altered thyroid hormone profile has been reported in patients with congestive
heart failure. However, information regarding the status of thyroid hormone
receptors in human failing cardiomyocytes is lacking. Therefore the expression
of thyroid hormone and beta-adrenergic receptors was investigated in human
ventricular cardiomyocytes isolated from patients with end-stage heart failure
(FM, n=12), or from tentative donors (C, n=4). The expression of thyroid
(TRalpha1, and TRbeta1) and beta-adrenergic receptors (ARB1 and ARB2) was
measured at both the gene, and at the protein level. In FM the reduced mRNA
expression of ARB1 (p<0.05, -37%) and ARB2 (p<0.05, -42%) was associated with a
reduction of the messenger for TRalpha1 (p<0.05, -85%) and TRalpha2 (p<0.05,
-73%). These findings were confirmed at the protein level for ARB1, ARB2 and
TRalpha1. These data reveal that in human heart failure the reduction of
beta-adrenergic receptors is associated with reduced expression of both TRalpha1
and TRalpha2 isoforms of thyroid hormone receptors.
DOI: 10.1016/j.bcp.2007.10.011
PMID: 18031713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22193721 | 1. EMBO J. 2012 Feb 15;31(4):856-69. doi: 10.1038/emboj.2011.466. Epub 2011 Dec
23.
A novel GRK2/HDAC6 interaction modulates cell spreading and motility.
Lafarga V(1), Aymerich I, Tapia O, Mayor F Jr, Penela P.
Author information:
(1)Departamento de Biología Molecular, and Centro de Biología Molecular 'Severo
Ochoa' (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
Cell motility and adhesion involves dynamic microtubule (MT)
acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major
cytoplasmic α-tubulin deacetylase. We identify G protein-coupled receptor kinase
2 (GRK2) as a key novel stimulator of HDAC6. GRK2, which levels inversely
correlate with the extent of α-tubulin acetylation in epithelial cells and
fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate
α-tubulin deacetylase activity. Remarkably, phosphorylation of GRK2 itself at
S670 specifically potentiates its ability to regulate HDAC6. GRK2 and HDAC6
colocalize in the lamellipodia of migrating cells, leading to local tubulin
deacetylation and enhanced motility. Consistently, cells expressing GRK2-K220R
or GRK2-S670A mutants, unable to phosphorylate HDAC6, exhibit highly acetylated
cortical MTs and display impaired migration and protrusive activity. Finally, we
find that a balanced, GRK2/HDAC6-mediated regulation of tubulin acetylation
differentially modulates the early and late stages of cellular spreading. This
novel GRK2/HDAC6 functional interaction may have important implications in
pathological contexts.
DOI: 10.1038/emboj.2011.466
PMCID: PMC3280560
PMID: 22193721 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23031622 | 1. Clin Ther. 2012 Oct;34(10):2051-60. doi: 10.1016/j.clinthera.2012.09.008. Epub
2012 Sep 29.
Dabigatran in clinical practice.
Nagarakanti R(1), Ellis CR.
Author information:
(1)Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center
Nashville, Tennessee 37232, USA.
BACKGROUND: Stroke and systemic thromboembolism remain critical causes of
mortality and morbidity in patients with paroxysmal or persistent atrial
fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor,
which provides stroke risk reduction for patients with nonvalvular atrial
fibrillation. Randomized clinical data demonstrate dabigatran to be an
alternative oral anticoagulant with an improved efficacy profile compared with
oral warfarin dose adjusted to an INR (international normalized ratio) target of
2.0 to 3.0.
OBJECTIVES: Our aim was to review the pharmacology, mechanism of action, drug
metabolism, and clinical trial data supporting dabigatran use.
METHODS: We reviewed all the major published clinical studies of dabigatran and
analyzed data regarding practical applications in selected clinical scenarios.
RESULTS: This review provides recommendations for clinicians regarding dosing
during invasive surgical procedures, transitioning off alternative
anticoagulants, and a discussion of storage and handling of the drug.
CONCLUSIONS: Our effort should facilitate the safe and effective use of
dabigatran in atrial fibrillation.
Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.
DOI: 10.1016/j.clinthera.2012.09.008
PMID: 23031622 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20075196 | 1. Am J Pathol. 2010 Mar;176(3):1256-70. doi: 10.2353/ajpath.2010.090188. Epub
2010 Jan 14.
Macrophage matrix metalloproteinase-9 mediates epithelial-mesenchymal transition
in vitro in murine renal tubular cells.
Tan TK(1), Zheng G, Hsu TT, Wang Y, Lee VW, Tian X, Wang Y, Cao Q, Wang Y,
Harris DC.
Author information:
(1)Centre for Transplantation and Renal Research, the University of Sydney at
Westmead Millennium Institute, Sydney, NSW 2145 Australia.
[email protected]
As a rich source of pro-fibrogenic growth factors and matrix metalloproteinases
(MMPs), macrophages are well-placed to play an important role in renal fibrosis.
However, the exact underlying mechanisms and the extent of macrophage
involvement are unclear. Tubular cell epithelial-mesenchymal transition (EMT) is
an important contributor to renal fibrosis and MMPs to induction of tubular cell
EMT. The aim of this study was to investigate the contribution of macrophages
and MMPs to induction of tubular cell EMT. The murine C1.1 tubular epithelial
cell line and primary tubular epithelial cells were cultured in activated
macrophage-conditioned medium (AMCM) derived from lipopolysaccharide-activated
J774 macrophages. MMP-9, but not MMP-2 activity was detected in AMCM.
AMCM-induced tubular cell EMT in C1.1 cells was inhibited by broad-spectrum MMP
inhibitor (GM6001), MMP-2/9 inhibitor, and in AMCM after MMP-9 removal by
monoclonal Ab against MMP-9. AMCM-induced EMT in primary tubular epithelial
cells was inhibited by MMP-2/9 inhibitor. MMP-9 induced tubular cell EMT in both
C1.1 cells and primary tubular epithelial cells. Furthermore, MMP-9 induced
tubular cell EMT in C1.1 cells to an extent similar to transforming growth
factor-beta. Transforming growth factor-beta-induced tubular cell EMT in C1.1
cells was inhibited by MMP-2/9 inhibitor. Our in vitro study provides evidence
that MMPs, specifically MMP-9, secreted by effector macrophages can induce
tubular cell EMT and thereby contribute to renal fibrosis.
DOI: 10.2353/ajpath.2010.090188
PMCID: PMC2832147
PMID: 20075196 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20948965 | 1. PLoS One. 2010 Oct 11;5(10):e13303. doi: 10.1371/journal.pone.0013303.
Deciphering heterogeneity in pig genome assembly Sscrofa9 by isochore and
isochore-like region analyses.
Zhang W(1), Wu W, Lin W, Zhou P, Dai L, Zhang Y, Huang J, Zhang D.
Author information:
(1)Bioinformatics Center, College of Life Science, Northwest A&F University,
Xianyang, Shaanxi, China.
BACKGROUND: The isochore, a large DNA sequence with relatively small GC
variance, is one of the most important structures in eukaryotic genomes.
Although the isochore has been widely studied in humans and other species,
little is known about its distribution in pigs.
PRINCIPAL FINDINGS: In this paper, we construct a map of long homogeneous genome
regions (LHGRs), i.e., isochores and isochore-like regions, in pigs to provide
an intuitive version of GC heterogeneity in each chromosome. The LHGR pattern
study not only quantifies heterogeneities, but also reveals some primary
characteristics of the chromatin organization, including the followings: (1) the
majority of LHGRs belong to GC-poor families and are in long length; (2) a high
gene density tends to occur with the appearance of GC-rich LHGRs; and (3) the
density of LINE repeats decreases with an increase in the GC content of LHGRs.
Furthermore, a portion of LHGRs with particular GC ranges (50%-51% and 54%-55%)
tend to have abnormally high gene densities, suggesting that biased gene
conversion (BGC), as well as time- and energy-saving principles, could be of
importance to the formation of genome organization.
CONCLUSION: This study significantly improves our knowledge of chromatin
organization in the pig genome. Correlations between the different biological
features (e.g., gene density and repeat density) and GC content of LHGRs provide
a unique glimpse of in silico gene and repeats prediction.
DOI: 10.1371/journal.pone.0013303
PMCID: PMC2952626
PMID: 20948965 [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/16623701 | 1. FEBS J. 2006 Apr;273(8):1637-48. doi: 10.1111/j.1742-4658.2006.05178.x.
Isochore structures in the chicken genome.
Gao F(1), Zhang CT.
Author information:
(1)Department of Physics, Tianjin University, China.
The availability of the complete chicken genome sequence provides an
unprecedented opportunity to study the global genome organization at the
sequence level. Delineating compositionally homogeneous G + C domains in DNA
sequences can provide much insight into the understanding of the organization
and biological functions of the chicken genome. A new segmentation algorithm,
which is simple and fast, has been proposed to partition a given genome or DNA
sequence into compositionally distinct domains. By applying the new segmentation
algorithm to the draft chicken genome sequence, the mosaic organization of the
chicken genome can be confirmed at the sequence level. It is shown herein that
the chicken genome is also characterized by a mosaic structure of isochores,
long DNA segments that are fairly homogeneous in the G + C content.
Consequently, 25 isochores longer than 2 Mb (megabases) have been identified in
the chicken genome. These isochores have a fairly homogeneous G + C content and
often correspond to meaningful biological units. With the aid of the technique
of cumulative GC profile, we proposed an intuitive picture to display the
distribution of segmentation points. The relationships between G + C content and
the distributions of genes (CpG islands, and other genomic elements) were
analyzed in a perceivable manner. The cumulative GC profile, equipped with the
new segmentation algorithm, would be an appropriate starting point for analyzing
the isochore structures of higher eukaryotic genomes.
DOI: 10.1111/j.1742-4658.2006.05178.x
PMID: 16623701 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9200812 | 1. Yeast. 1997 Jun 15;13(7):621-37. doi:
10.1002/(SICI)1097-0061(19970615)13:7<621::AID-YEA121>3.0.CO;2-U.
The AFT1 transcriptional factor is differentially required for expression of
high-affinity iron uptake genes in Saccharomyces cerevisiae.
Casas C(1), Aldea M, Espinet C, Gallego C, Gil R, Herrero E.
Author information:
(1)Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat
de Lleida, Spain.
High-affinity iron uptake in Saccharomyces cerevisiae involves the
extracytoplasmic reduction of ferric ions by FRE1 and FRE2 reductases. Ferrous
ions are then transported across the plasma membrane through the FET3
oxidase-FTR1 permease complex. Expression of the high-affinity iron uptake genes
is induced upon iron deprivation. We demonstrate that AFT1 is differentially
involved in such regulation. Aft1 protein is required for maintaining detectable
non-induced level of FET3 expression and for induction of FRE2 in iron
starvation conditions. On the contrary, FRE1 mRNA induction is normal in the
absence of Aft1, although the existence of AFT1 point mutations causing
constitutive expression of FRE1 (Yamaguchi-Iwai et al., EMBO J. 14: 1231-1239,
1995) indicates that Aft1 may also participate in FRE1 expression in a
dispensable way. The alterations in the basal levels of expression of the
high-affinity iron uptake genes may explain why the AFT1 mutant is unable to
grow on respirable carbon sources. Overexpression of AFT1 leads to growth arrest
of the G1 stage of the cell cycle. Aft1 is a transcriptional activator that
would be part of the different transcriptional complexes interacting with the
promoter of the high-affinity iron uptake genes. Aft1 displays phosphorylation
modifications depending on the growth stage of the cells, and it might link
induction of genes for iron uptake to other metabolically dominant requirement
for cell growth.
DOI: 10.1002/(SICI)1097-0061(19970615)13:7<621::AID-YEA121>3.0.CO;2-U
PMID: 9200812 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20940043 | 1. Cell Signal. 2011 May;23(5):763-71. doi: 10.1016/j.cellsig.2010.10.014. Epub
2010 Oct 19.
The ins and outs of tubulin acetylation: more than just a post-translational
modification?
Perdiz D(1), Mackeh R, Poüs C, Baillet A.
Author information:
(1)Univ. Paris Sud-11, UPRES EA4530 IFR IPSIT, Faculté de Pharmacie, 5 rue JB
Clément 92296 Châtenay-Malabry, France.
Microtubules are highly dynamic polymers of α/β tubulin heterodimers that play
key roles in cell division and in organizing cell cytoplasm. Although they have
been discovered more than two decades ago, tubulin post-translational
modifications recently gained a new interest as their role was increasingly
highlighted in neuron differentiation and neurodegenerative disorders. Here, we
specifically focus on tubulin acetylation from its discovery to recent studies
that provide new insights into how it is regulated in health and disease and how
it impacts microtubule functions. Even though new mechanisms involving tubulin
acetylation are regularly being uncovered, the molecular links between its
location inside the microtubule lumen and its regulators and effectors is still
poorly understood. This review highlights the emerging roles of tubulin
acetylation in multiple cellular functions, ranging from cell motility, cell
cycle progression or cell differentiation to intracellular trafficking and
signalling. It also points out that tubulin acetylation should no longer be seen
as a passive marker of microtubule stability, but as a broad regulator of
microtubule functions.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cellsig.2010.10.014
PMID: 20940043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22486326 | 1. Ophthalmic Genet. 2012 Sep;33(3):159-60. doi: 10.3109/13816810.2011.610860.
Epub 2012 Apr 9.
Ophthalmologic abnormalities in Mowat-Wilson syndrome and a mutation in ZEB2.
Ariss M(1), Natan K, Friedman N, Traboulsi EI.
Author information:
(1)Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial
appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the
corpus callosum, Hirschsprung disease, congenital heart disease, and genital
anomalies. Ophthalmological abnormalities have been rarely described in patients
with this condition which is caused by mutations in the ZEB2 gene. We report a
9-year-old female with this syndrome who has severe ocular abnormalities
including bilateral microphthalmia, cataract, and retinal aplasia.
DOI: 10.3109/13816810.2011.610860
PMID: 22486326 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7720713 | 1. EMBO J. 1995 Mar 15;14(6):1231-9. doi: 10.1002/j.1460-2075.1995.tb07106.x.
AFT1: a mediator of iron regulated transcriptional control in Saccharomyces
cerevisiae.
Yamaguchi-Iwai Y(1), Dancis A, Klausner RD.
Author information:
(1)Cell Biology and Metabolism Branch, National Institute of Child Health and
Human Development, National Institutes of Health, Bethesda, MD, USA.
Using a scheme for selecting mutants of Saccharomyces cerevisiae with
abnormalities of iron metabolism, we have identified a gene, AFT1, that mediates
the control of iron uptake. AFT1 encodes a 78 kDa protein with a highly basic
amino terminal domain and a glutamine-rich C-terminal domain, reminiscent of
transcriptional activators. The protein also contains an amino terminal and a
C-terminal region with 10% His residues. A dominant mutant allele of this gene,
termed AFT1-1up, results in high levels of ferric reductase and ferrous iron
uptake that are not repressed by exogenous iron. The increased iron uptake is
associated with enhanced susceptibility to iron toxicity. These effects may be
explained by the failure of iron to repress transcription of FRE1, FRE2 and
FET3. FRE1 and FRE2 encode plasma membrane ferric reductases, obligatory for
ferric iron assimilation, and FET3 encodes a copper-dependent
membrane-associated oxidase required for ferrous iron uptake. Conversely, a
strain with interruption of the AFT1 gene manifests low ferric reductase and
ferrous iron uptake and is susceptible to iron deprivation, because of deficient
expression of FRE1 and negligible expression of FRE2 and FET3. Thus, AFT1
functions to activate transcription of target genes in response to iron
deprivation and thereby plays a central role in iron homeostasis.
DOI: 10.1002/j.1460-2075.1995.tb07106.x
PMCID: PMC398200
PMID: 7720713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14739928 | 1. EMBO J. 2004 Jan 28;23(2):333-42. doi: 10.1038/sj.emboj.7600043. Epub 2004 Jan
22.
Nhp6 facilitates Aft1 binding and Ssn6 recruitment, both essential for FRE2
transcriptional activation.
Fragiadakis GS(1), Tzamarias D, Alexandraki D.
Author information:
(1)Institute of Molecular Biology and Biotechnology-FORTH, University of Crete,
Vassilika Vouton, Heraklion, Crete, Greece.
We found Nhp6a/b yeast HMG-box chromatin-associated architectural factors and
Ssn6 (Cyc8) corepressor to be crucial transcriptional coactivators of FRE2 gene.
FRE2 encoding a plasma membrane ferric reductase is induced by the
iron-responsive, DNA-binding, transcriptional activator Aft1. We have shown that
Nhp6 interacts directly with the Aft1 N-half, including the DNA-binding region,
to facilitate Aft1 binding at FRE2 UAS. Ssn6 also interacts directly with the
Aft1 N-half and is recruited on FRE2 promoter only in the presence of both Aft1
and Nhp6. This Nhp6/Ssn6 role in Aft1-mediated transcription is FRE2 promoter
context specific, and both regulators are required for activation-dependent
chromatin remodeling. Our results provide the first in vivo biochemical evidence
for nonsequence-specific HMG-box protein-facilitated recruitment of a yeast
gene-specific transactivator to its DNA target site and for Nhp6-mediated Ssn6
promoter recruitment. Ssn6 has an explicitly coactivating role on FRE2 promoter
only upon induction. Therefore, transcriptional activation in response to iron
availability involves multiple protein interactions between the Aft1
iron-responsive DNA-binding factor and global regulators such as Nhp6 and Ssn6.
DOI: 10.1038/sj.emboj.7600043
PMCID: PMC1271752
PMID: 14739928 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17057231 | 1. Genetics. 2007 Jan;175(1):421-8. doi: 10.1534/genetics.106.064386. Epub 2006
Oct 22.
The rate, not the spectrum, of base pair substitutions changes at a GC-content
transition in the human NF1 gene region: implications for the evolution of the
mammalian genome structure.
Schmegner C(1), Hoegel J, Vogel W, Assum G.
Author information:
(1)Institut für Humangenetik, Universität Ulm, D-89081 Ulm, Germany.
The human genome is composed of long stretches of DNA with distinct GC contents,
called isochores or GC-content domains. A boundary between two GC-content
domains in the human NF1 gene region is also a boundary between domains of
early- and late-replicating sequences and of regions with high and low
recombination frequencies. The perfect conservation of the GC-content
distribution in this region between human and mouse demonstrates that GC-content
stabilizing forces must act regionally on a fine scale at this locus. To further
elucidate the nature of these forces, we report here on the spectrum of human
SNPs and base pair substitutions between human and chimpanzee. The results show
that the mutation rate changes exactly at the GC-content transition zone from
low values in the GC-poor sequences to high values in GC-rich ones. The GC
content of the GC-poor sequences can be explained by a bias in favor of GC > AT
mutations, whereas the GC content of the GC-rich segment may result from a
fixation bias in favor of AT > GC substitutions. This fixation bias may be
explained by direct selection by the GC content or by biased gene conversion.
DOI: 10.1534/genetics.106.064386
PMCID: PMC1775011
PMID: 17057231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22246645 | 1. Am J Med Genet A. 2012 Feb;158A(2):358-66. doi: 10.1002/ajmg.a.34405. Epub
2012 Jan 13.
The behavioral phenotype of Mowat-Wilson syndrome.
Evans E(1), Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M.
Author information:
(1)Department of Developmental Disability Neuropsychiatry, School of Psychiatry,
University of New South Wales, Sydney, New South Wales, Australia.
[email protected]
Mowat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of
the ZEB2 gene. It is characterized by a distinctive facial appearance in
association with intellectual disability (ID) and variable other features
including agenesis of the corpus callosum, seizures, congenital heart defects,
microcephaly, short stature, hypotonia, and Hirschsprung disease. The current
study investigated the behavioral phenotype of MWS. Parents and carers of 61
individuals with MWS completed the Developmental Behavior Checklist. Data were
compared with those for individuals selected from an epidemiological sample of
people with ID from other causes. The behaviors associated with MWS included a
high rate of oral behaviors, an increased rate of repetitive behaviors, and an
under-reaction to pain. Other aspects of the MWS behavioral phenotype are
suggestive of a happy affect and sociable demeanor. Despite this, those with MWS
displayed similarly high levels of behavioral problems as those with
intellectual disabilities from other causes, with over 30% showing clinically
significant levels of behavioral or emotional disturbance. These findings have
the potential to expand our knowledge of the role of the ZEB2 gene during
neurodevelopment. Furthermore, they are a foundation for informing interventions
and management options to enhance the independence and quality of life for
persons with MWS.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.34405
PMID: 22246645 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17389148 | 1. Gene. 2007 Jun 1;394(1-2):53-60. doi: 10.1016/j.gene.2007.01.028. Epub 2007
Feb 16.
Discovering isochores by least-squares optimal segmentation.
Haiminen N(1), Mannila H.
Author information:
(1)HIIT Basic Research Unit, Department of Computer Science, University of
Helsinki, Finland. [email protected]
The isochore structure of a genome is observable by variation in the G+C
(guanine and cytosine) content within and between the chromosomes. Describing
the isochore structure of vertebrate genomes is a challenging task, and many
computational methods have been developed and applied to it. Here we apply a
well-known least-squares optimal segmentation algorithm to isochore discovery.
The algorithm finds the best division of the sequence into k pieces, such that
the segments are internally as homogeneous as possible. We show how this simple
segmentation method can be applied to isochore discovery using as input the G+C
content of sliding windows on the sequence. To evaluate the performance of this
segmentation technique on isochore detection, we present results from segmenting
previously studied isochore regions of the human genome. Detailed results on the
MHC locus, on parts of chromosomes 21 and 22, and on a 100 Mb region from
chromosome 1 are similar to previously suggested isochore structures. We also
give results on segmenting all 22 autosomal human chromosomes. An advantage of
this technique is that oversegmentation of G+C rich regions can generally be
avoided. This is because the technique concentrates on greater global, instead
of smaller local, differences in the sequence composition. The effect is further
emphasized by a log-transformation of the data that lowers the high variance
that is observed in G+C rich regions. We conclude that the least-squares optimal
segmentation method is computationally efficient and yields results close to
previous biologically motivated isochore structures.
DOI: 10.1016/j.gene.2007.01.028
PMID: 17389148 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21106759 | 1. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6. doi:
10.1073/pnas.1016071107. Epub 2010 Nov 24.
Histone H3K27ac separates active from poised enhancers and predicts
developmental state.
Creyghton MP(1), Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna
J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R.
Author information:
(1)Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Comment in
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21240-1. doi:
10.1073/pnas.1016297108.
Developmental programs are controlled by transcription factors and chromatin
regulators, which maintain specific gene expression programs through epigenetic
modification of the genome. These regulatory events at enhancers contribute to
the specific gene expression programs that determine cell state and the
potential for differentiation into new cell types. Although enhancer elements
are known to be associated with certain histone modifications and transcription
factors, the relationship of these modifications to gene expression and
developmental state has not been clearly defined. Here we interrogate the
epigenetic landscape of enhancer elements in embryonic stem cells and several
adult tissues in the mouse. We find that histone H3K27ac distinguishes active
enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This
indicates that the amount of actively used enhancers is lower than previously
anticipated. Furthermore, poised enhancer networks provide clues to unrealized
developmental programs. Finally, we show that enhancers are reset during nuclear
reprogramming.
DOI: 10.1073/pnas.1016071107
PMCID: PMC3003124
PMID: 21106759 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/19215041 | 1. Am J Med Genet A. 2009 Mar;149A(3):417-26. doi: 10.1002/ajmg.a.32693.
Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian
patients and review of the literature.
Garavelli L(1), Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R,
Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano
F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti
L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R,
Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S,
Wakamatsu N, Neri G.
Author information:
(1)Clinical Genetics Unit, Obstetric and Pediatric Department, S. Maria Nuova
Hospital, Reggio Emilia, Italy. [email protected]
Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by
heterozygous mutations or deletions of the ZEB2 gene, and characterized by
typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung
disease, and multiple congenital anomalies, including genital anomalies
(particularly hypospadias in males), congenital heart defects, agenesis of the
corpus callosum, and eye defects. Since the first delineation by Mowat et al.
[Mowat et al. (1998); J Med Genet 35:617-623], approximately 179 patients with
ZEB2 mutations, deletions or cytogenetic abnormalities have been reported
primarily from Europe, Australia and the United States. Genetic defects include
chromosome 2q21-q23 microdeletions (or different chromosome rearrangements) in
few patients, and ZEB2 mutations in most. We report on clinical and genetic data
from 19 Italian patients, diagnosed within the last 5 years, including six
previously published, and compare them with patients already reported. The main
purpose of this review is to underline a highly consistent phenotype and to
highlight the phenotypic evolution occurring with age, particularly of the
facial characteristics. The prevalence of MWS is likely to be underestimated.
Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with
age can improve the detection rate of this condition.
2009 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.32693
PMID: 19215041 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12639993 | 1. J Clin Invest. 2003 Mar;111(6):869-76. doi: 10.1172/JCI17892.
Human phospholamban null results in lethal dilated cardiomyopathy revealing a
critical difference between mouse and human.
Haghighi K(1), Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC,
Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW 2nd, MacLennan DH,
Kremastinos DT, Kranias EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati,
College of Medicine, Cincinnati, Ohio 45267, USA.
Comment in
J Clin Invest. 2003 Mar;111(6):801-3. doi: 10.1172/JCI18153.
In human disease and experimental animal models, depressed Ca(2+) handling in
failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum
(SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN)
or expression of dominant-negative PLN mutants enhances SR and cardiac function,
but effects of PLN mutations in humans are unknown. Here, a T116G point
mutation, substituting a termination codon for Leu-39 (L39stop), was identified
in two families with hereditary heart failure. The heterozygous individuals
exhibited hypertrophy without diminished contractile performance. Strikingly,
both individuals homozygous for L39stop developed dilated cardiomyopathy and
heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50%
reduction in PLN mRNA and no detectable PLN protein were noted in one explanted
heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK)
293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR
Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was
expressed, it was misrouted to the cytosol or plasma membrane. These findings
describe a naturally-occurring loss-of-function human PLN mutation (PLN null).
In contrast to reported benefits of PLN ablation in mouse heart failure, humans
lacking PLN develop lethal dilated cardiomyopathy.
DOI: 10.1172/JCI17892
PMCID: PMC153772
PMID: 12639993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21893004 | 1. Ugeskr Laeger. 2011 Sep 5;173(36):2199-200.
[Mowat-Wilson syndrome: a report of three Danish cases].
[Article in Danish]
Nissen KB(1), Søndergaard C, Thelle T, Møller RS.
Author information:
(1)Pædiatrisk Afdeling, Regionshospitalet Herning, 7400 Herning, Denmark.
[email protected]
Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability
syndrome characterised by unique facial features and congenital anomalies such
as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and
urinary tract anomalies. Some cases also present epilepsy, growth retardation
and microcephaly. The syndrome is caused by mutations or deletions of the ZEB2
gene at chromosome 2q22-q23. MWS was first described in 1998 and until now
approximately 180 cases have been reported worldwide. We report the first three
molecularly confirmed Danish cases with MWS.
PMID: 21893004 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21957361 | 1. Indian J Hum Genet. 2007 Sep;13(3):122-4. doi: 10.4103/0971-6866.38988.
Mowat-Wilson syndrome in a Moroccan consanguineous family.
Ratbi I(1), Elalaoui CS, Dastot-Le MF, Goossens M, Giurgea I, Sefiani A.
Author information:
(1)Department of Medical Genetics, National Institute of Health, 27 Avenue Ibn
Batouta, Rabat, Morocco.
Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly
syndrome characterized by a typical facies, developmental delay, epilepsy, and
variable congenital malformations, including Hirschsprung disease, urogenital
anomalies, congenital heart disease, and agenesis of the corpus callosum. This
disorder is sporadic and is caused by heterozygous mutations or deletions of the
ZFHX1B gene located in the 2q22 region. We report here the first Moroccan
patient, born to consanguineous parents, with Mowat-Wilson syndrome, due to a de
novo, unreported mutation of the ZFHX1B gene.
DOI: 10.4103/0971-6866.38988
PMCID: PMC3168139
PMID: 21957361
Conflict of interest statement: Conflict of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/22672556 | 1. BMC Cancer. 2012 Jun 6;12:217. doi: 10.1186/1471-2407-12-217.
Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other
malignancies: case report and review of the literature.
Kast K(1), Krause M, Schuler M, Friedrich K, Thamm B, Bier A, Distler W, Krüger
S.
Author information:
(1)Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe,
Universitätsklinikum Carl Gustav Carus, Fetscherstr, 74, 01307, Dresden,
Germany. [email protected]
BACKGROUND: Li-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited
tumour predisposition syndrome associated with heterozygous germline mutations
in the TP53 gene. Patients with LFS are at a high risk to develop early-onset
breast cancer and multiple malignancies, among which sarcomas are the most
common. A high incidence of childhood tumours and close to 100% penetrance has
been described. Knowledge of the genetic status of the TP53 gene in these
patients is critical not only due to the increased risk of malignancies, but
also because of the therapeutic implications, since a higher rate of
radiation-induced secondary tumours in these patients has been observed.
CASE REPORT: We report a patient with LFS harbouring heterozygous, pathogenic
TP53 germline mutation, who was affected by four synchronous malignancies at the
age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer
and a periadrenal liposarcoma. Radiological treatments and a surveillance
program were adjusted according to recommendations for LFS patients.
CONCLUSION: Management of tumour treatment of patients with LFS is different to
the general population because of their risk for secondary cancers in the
radiation field. Screening procedures should take a possibly elevated risk for
radiation induced cancer into account.
DOI: 10.1186/1471-2407-12-217
PMCID: PMC3487792
PMID: 22672556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24401652 | 1. Orphanet J Rare Dis. 2014 Jan 8;9:2. doi: 10.1186/1750-1172-9-2.
ZEB2, a new candidate gene for asplenia.
Pons L, Dupuis-Girod S(1), Cordier MP, Edery P, Rossi M.
Author information:
(1)Hospices Civils de Lyon, Groupe Hospitalier Est, Service de Génétique et
Centre de référence des anomalies du développement, Bron F-69677, France.
[email protected].
Primary asplenia is a rare condition with poorly known etiology. Mowat-Wilson
syndrome (MWS) is characterized by typical facial dysmorphisms, intellectual
disability, microcephaly, epilepsy and the possible presence of internal organ
malformations. It is caused by heterozygous mutations or deletions in the ZEB2
gene. Nearly 180 patients have been reported to date, but only one with
asplenia. We report here spleen hypo/aplasia in 4 out of 6 MWS patients, with
severe infectious complications for 3 of them. Our report shows that spleen
hypo/aplasia is part of the MWS phenotype and makes ZEB2 a possible candidate
gene for primary asplenia.
DOI: 10.1186/1750-1172-9-2
PMCID: PMC3891986
PMID: 24401652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11877447 | 1. J Biol Chem. 2002 May 24;277(21):18914-8. doi: 10.1074/jbc.M200949200. Epub
2002 Mar 4.
Subcellular localization of Aft1 transcription factor responds to iron status in
Saccharomyces cerevisiae.
Yamaguchi-Iwai Y(1), Ueta R, Fukunaka A, Sasaki R.
Author information:
(1)Department of Applied Molecular Biology, Graduate School of Biostudies, Kyoto
University, Sakyo-ku, Kyoto 606-8502, Japan. [email protected]
The Aft1 transcription factor regulates the iron regulon in response to iron
availability in Saccharomyces cerevisiae. Aft1 activates a battery of genes
required for iron uptake under iron-starved conditions, whereas Aft1 function is
inactivated under iron-replete conditions. Previously, we have shown that
iron-regulated DNA binding by Aft1 is responsible for the controlled expression
of target genes. Here we show that this iron-regulated DNA binding by Aft1 is
not due to the change in the total expression level of Aft1 or alteration of DNA
binding activity. Rather, nuclear localization of Aft1 responds to iron status,
leading to iron-regulated expression of the target genes. We identified the
nuclear export signal (NES)-like sequence in the AFT1 open reading frame.
Mutation of the NES-like sequence causes nuclear retention of Aft1 and the
constitutive activation of Aft1 function independent of the iron status of the
cells. These results suggest that the nuclear export of Aft1 is critical for
ensuring iron-responsive transcriptional activation of the Aft1 regulon and that
the nuclear import/export systems are involved in iron sensing by Aft1 in S.
cerevisiae.
DOI: 10.1074/jbc.M200949200
PMID: 11877447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20428734 | 1. Singapore Med J. 2010 Mar;51(3):e54-7.
Mowat-Wilson syndrome: the first two Malaysian cases.
Balasubramaniam S(1), Keng WT, Ngu LH, Michel LG, Irina G.
Author information:
(1)Department of Clinical Genetics, Pediatric Institute, Kuala Lumpur Hospital,
Jalan Pahang, Kuala Lumpur 50586, Malaysia. [email protected]
Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a
multiple congenital anomaly syndrome characterised by a typical facial gestalt,
Hirschsprung disease or severe constipation, genitourinary anomaly, congenital
heart defects, agenesis of corpus callosum and eye defects. Some cases also
present with epilepsy, growth retardation with microcephaly and speech
impairment. MWS was first described in 1998 by Mowat et al, and approximately
180 cases have been reported as of August 2008. The syndrome occurs as a result
of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox
2 gene, ZEB2, previously called ZFHX1B (SIP1). Most cases reported so far were
sporadic occurrences; however, rare cases of sibling recurrence have been cited.
The facial phenotype is particularly important for the initial clinical
diagnosis and provides the hallmark, warranting ZEB2 mutational analysis even in
the absence of Hirschsprung disease. We present the first two molecularly
confirmed Malaysian MWS patients, one of whom has a novel mutation.
PMID: 20428734 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7981072 | 1. Br J Cancer. 1994 Dec;70(6):1176-81. doi: 10.1038/bjc.1994.468.
Linkage studies in a Li-Fraumeni family with increased expression of p53 protein
but no germline mutation in p53.
Birch JM(1), Heighway J, Teare MD, Kelsey AM, Hartley AL, Tricker KJ, Crowther
D, Lane DP, Santibáñez-Koref MF.
Author information:
(1)University of Manchester, CRC Paediatric & Familial Cancer Research Group,
Christie Hospital, UK.
We report a family with the Li-Fraumeni syndrome (LFS) in whom we have been
unable to detect a mutation in the coding sequence of the p53 gene. Analysis of
linkage to three polymorphic markers within p53 enabled direct involvement of
p53 to be excluded. This is the first example of a LFS family in whom exclusion
of p53 has been possible. Four affected members of the family with sarcoma or
premenopausal breast cancer showed increased expression of p53 protein in their
normal tissues as detected by immunohistochemistry. It therefore appears that
the LFS phenotype has been conferred by an aberrant gene, showing a dominant
pattern of inheritance, which may be acting to compromise normal p53 function
rather than by a mutation in p53 itself. In order to try to determine the
chromosomal location of this putative gene, we have carried out studies of
linkage to candidate loci. By these means we have excluded involvement of Rb1
and BRCA1 on chromosomes 13q and 17q respectively. The MDM2 oncogene on
chromosome 12q was considered to be the prime candidate as MDM2 is amplified in
sarcomas and the MDM2 product binds to p53. Furthermore, p53 mutation and
amplification of MDM2 have been shown to be mutually exclusive events in tumour
development. Linkage analysis to two polymorphic markers within MDM2 yielded a
three-point LOD score of -5.4 at a recombination fraction theta equal to zero.
Therefore MDM2 could be excluded. It is possible that the gene which is
responsible for cancer susceptibility in this family, possibly via interaction
with p53, will be important in the histogenesis of breast cancer in general. We
are now carrying out further studies to locate and identify this gene.
DOI: 10.1038/bjc.1994.468
PMCID: PMC2033684
PMID: 7981072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20301585 | 1. Mowat-Wilson Syndrome.
Adam MP(1), Conta J(2), Bean LJH(3).
In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW,
Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of
Washington, Seattle; 1993–2024.
2007 Mar 28 [updated 2019 Jul 25].
Author information:
(1)Professor of Pediatrics, Division of Genetic Medicine, Department of
Pediatrics, University of Washington, Seattle, Washington
(2)Department of Laboratories, Seattle Children’s Hospital, Seattle, Washington
(3)PerkinElmer Genomics, Inc, Pittsburgh, Pennsylvania
CLINICAL CHARACTERISTICS: Mowat-Wilson syndrome (MWS) is characterized by
distinctive facial features (widely spaced eyes, broad eyebrows with a medial
flare, low-hanging columella, prominent or pointed chin, open-mouth expression,
and uplifted earlobes with a central depression), congenital heart defects with
predilection for abnormalities of the pulmonary arteries and/or valves,
Hirschsprung disease or chronic constipation, genitourinary anomalies
(particularly hypospadias in males), and hypogenesis or agenesis of the corpus
callosum. Most affected individuals have moderate-to-severe intellectual
disability. Speech is typically limited to a few words or is absent, with
relative preservation of receptive language skills. Growth restriction with
microcephaly and seizure disorder are also common. Most affected people have a
happy demeanor and a wide-based gait that can sometimes be confused with
Angelman syndrome.
DIAGNOSIS/TESTING: The diagnosis of MWS is established in a proband with classic
dysmorphic facial features and developmental delay / intellectual disability
and/or a heterozygous pathogenic variant in ZEB2 identified by molecular genetic
testing.
MANAGEMENT: Treatment of manifestations: Care by the appropriate specialist for
dental anomalies, seizures, ocular abnormalities, congenital heart defects,
chronic constipation, Hirschsprung disease, genitourinary abnormalities, and
pectus anomalies of the chest and/or foot/ankle anomalies; educational
intervention and speech therapy beginning in infancy. Surveillance: Annual eye
examination in childhood to monitor for strabismus and refractive errors;
monitoring for otitis media; regular developmental assessments to plan/refine
educational interventions; periodic reevaluation by a clinical geneticist.
GENETIC COUNSELING: MWS is an autosomal dominant disorder caused by a pathogenic
variant in ZEB2, a heterozygous deletion of 2q22.3 involving ZEB2, or (rarely) a
chromosome rearrangement that disrupts ZEB2. Almost all individuals reported to
date have been simplex cases (i.e., a single occurrence in a family) resulting
from a de novo genetic alteration; rarely, recurrence in a family has been
reported when a parent has a low level of somatic or presumed germline mosaicism
for a MWS-causing pathogenic variant. Individuals with MWS are not known to
reproduce. Once the causative genetic alteration has been identified in the
proband, prenatal testing may be offered to parents of a child with MWS because
of the recurrence risk associated with the possibility of parental mosaicism or
a balanced chromosome rearrangement.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a
registered trademark of the University of Washington, Seattle. All rights
reserved.
PMID: 20301585 |
http://www.ncbi.nlm.nih.gov/pubmed/18792984 | 1. Am J Med Genet A. 2008 Oct 1;146A(19):2501-11. doi: 10.1002/ajmg.a.32476.
Agenesis and dysgenesis of the corpus callosum: clinical, genetic and
neuroimaging findings in a series of 41 patients.
Schell-Apacik CC(1), Wagner K, Bihler M, Ertl-Wagner B, Heinrich U, Klopocki E,
Kalscheuer VM, Muenke M, von Voss H.
Author information:
(1)Institute of Social Pediatrics and Adolescent Medicine of the University of
Munich, München, Germany. [email protected]
Agenesis of the corpus callosum (ACC) is among the most frequent human brain
malformations with an incidence of 0.5-70 in 10,000. It is a heterogeneous
condition, for which several different genetic causes are known, for example,
ACC as part of monogenic syndromes or complex chromosomal rearrangements. We
systematically evaluated the data of 172 patients with documented corpus
callosum abnormalities in the records, and 23 patients with chromosomal
rearrangements known to be associated with corpus callosum changes. All
available neuroimaging data, including CT and MRI, were re-evaluated following a
standardized protocol. Whenever feasible chromosome and subtelomere analyses as
well as molecular genetic testing were performed in patients with disorders of
the corpus callosum in order to identify a genetic diagnosis. Our results showed
that 41 patients with complete absence (agenesis of the corpus callosum-ACC) or
partial absence (dysgenesis of the corpus callosum-DCC) were identified. Out of
these 28 had ACC, 13 had DCC. In 11 of the 28 patients with ACC, the following
diagnoses could be established: Mowat-Wilson syndrome (n = 2), Walker-Warburg
syndrome (n = 1), oro-facial-digital syndrome type 1 (n = 1), and chromosomal
rearrangements (n = 7), including a patient with an apparently balanced
reciprocal translocation, which led to the disruption and a predicted loss of
function in the FOXG1B gene. The cause of the ACC in 17 patients remained
unclear. In 2 of the 13 patients with DCC, unbalanced chromosomal rearrangements
could be detected (n = 2), while the cause of DCC in 11 patients remained
unclear. In our series of cases a variety of genetic causes of disorders of the
corpus callosum were identified with cytogenetic anomalies representing the most
common underlying etiology.
Copyright 2008 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.32476
PMCID: PMC2774850
PMID: 18792984 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9152623 | 1. Endocr J. 1997 Feb;44(1):117-20. doi: 10.1507/endocrj.44.117.
A case of active acromegalic woman with a marked increase in serum insulin-like
growth factor-1 levels after delivery.
Okada Y(1), Morimoto I, Ejima K, Yoshida K, Kashimura M, Fujihira T, Eto S.
Author information:
(1)First Department of Internal Medicine, University of Occupational and
Environmental Health Japan, School of Medicine, Fukuoka, Japan.
Pregnancy in a woman with active acromegaly is very rare, because amenorrhea,
due to hyperprolactinemia and disturbed pituitary gonadotropin secretion may
cause infertility. We report a 28-year-old pregnant woman with untreated
acromegaly, who was followed up from early pregnancy to delivery. Her pregnancy
was uneventful, and she went into spontaneous labor at 38 weeks and delivered a
normal infant. Her serum GH levels were further increased in late pregnancy,
followed by decreased in postpartum periods, which may be associated with
enlargement of pituitary adenoma during pregnancy. In contrast with serum GH,
her serum insulin-like growth factor-1 (IGF-1) levels were dissociated with her
serum GH levels during late pregnant and postpartum period. Her serum GH and
IGF-1 levels in late pregnancy were different from the levels in pregnant women
with acromegaly reported previously.
DOI: 10.1507/endocrj.44.117
PMID: 9152623 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25650801 | 1. Nat Rev Mol Cell Biol. 2015 Mar;16(3):144-54. doi: 10.1038/nrm3949. Epub 2015
Feb 4.
The selection and function of cell type-specific enhancers.
Heinz S(1), Romanoski CE(2), Benner C(1), Glass CK(3).
Author information:
(1)Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La
Jolla, San Diego, California 92037, USA.
(2)Department of Cellular and Molecular Medicine, University of California, San
Diego, 9500 Gilman Drive, La Jolla, San Diego, California 92093, USA.
(3)1] Department of Cellular and Molecular Medicine, University of California,
San Diego, 9500 Gilman Drive, La Jolla, San Diego, California 92093, USA. [2]
Department of Medicine, University of California, San Diego, 9500 Gilman Drive,
La Jolla, San Diego, California 92093, USA.
The human body contains several hundred cell types, all of which share the same
genome. In metazoans, much of the regulatory code that drives cell type-specific
gene expression is located in distal elements called enhancers. Although
mammalian genomes contain millions of potential enhancers, only a small subset
of them is active in a given cell type. Cell type-specific enhancer selection
involves the binding of lineage-determining transcription factors that prime
enhancers. Signal-dependent transcription factors bind to primed enhancers,
which enables these broadly expressed factors to regulate gene expression in a
cell type-specific manner. The expression of genes that specify cell type
identity and function is associated with densely spaced clusters of active
enhancers known as super-enhancers. The functions of enhancers and
super-enhancers are influenced by, and affect, higher-order genomic
organization.
DOI: 10.1038/nrm3949
PMCID: PMC4517609
PMID: 25650801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15769782 | 1. Eur Heart J. 2005 Apr;26(8):794-803. doi: 10.1093/eurheartj/ehi193. Epub 2005
Mar 15.
Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin
heavy chain gene.
Villard E(1), Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N,
Komajda M.
Author information:
(1)INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013
Paris, France. [email protected]
Comment in
Eur Heart J. 2005 Apr;26(8):751-4. doi: 10.1093/eurheartj/ehi208.
AIMS: Familial dilated cardiomyopathy (FDCM) is associated with mutations in
more than 10 genes, but genes mutation frequencies and associated clinical
features remain largely unknown. Here, we performed a mutation analysis of four
genes involved in FDCM in a population of idiopathic DCM.
METHODS AND RESULTS: A SSCP and sequencing mutation screening of all the exons
coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene),
phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL
gene) were performed in 96 independent patients (54 familial and 42 sporadic).
It led to the identification of eight heterozygous mutations, seven new ones in
MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five
familial and two sporadic cases) substitute residues located either in the head
(I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the
protein. DCM was not associated with skeletal myopathy or conduction defects in
any patients. Contrasting clinical features were observed between MYH7 and TNNT2
mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03),
penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac
event was higher (P<0.04).
CONCLUSION: We have identified seven mutations in MYH7, one in TNNT2, and none
in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently
mutated gene in our FDCM population (approximately 10%), and mutation carriers
present with delayed onset, in contrast to TNNT2.
DOI: 10.1093/eurheartj/ehi193
PMID: 15769782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22763610 | 1. Invest New Drugs. 2013 Jun;31(3):642-52. doi: 10.1007/s10637-012-9848-0. Epub
2012 Jul 5.
Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and
cisplatin (PLF) in patients with advanced gastric and esophagogastric
adenocarcinomas.
Trarbach T(1), Przyborek M, Schleucher N, Heeger S, Lüpfert C, Vanhoefer U.
Author information:
(1)Department of Medicine (Cancer Research), West German Cancer Center,
University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
[email protected]
BACKGROUND: To evaluate the safety and tolerability of two different weekly
doses of the fully humanized epidermal growth factor receptor (EGFR)-targeting
monoclonal antibody matuzumab combined with high-dose 5-fluorouracil, leucovorin
and cisplatin (PLF) in the first-line treatment of patients with EGFR-positive
advanced gastric and esophagogastric adenocarcinomas.
METHODS: Patients were treated in two matuzumab dose groups with the first
cohort of patients receiving 400 mg matuzumab in combination with PLF. Based on
the safety observations the next cohort of patients received 800 mg matuzumab.
The study was conducted in two parts, with phase A, designed to assess the
safety and tolerability of the combination, and phase B designed to be a
treatment continuation for those patients benefiting from treatment. Treatment
cycles were 7 weeks each. Each patient received the dose of matuzumab they were
assigned to at study entry for the duration of the study.
RESULTS: Fifteen EGFR-positive patients were enrolled into the two matuzumab
dose groups; 400 mg dose n=7; 800 mg dose n=8. All patients experienced at least
one adverse event (AE). No patient experienced any serious AE which was
considered to be related to matuzumab. Two grade 3 AEs possibly related to
matuzumab occurred in 2 different patients (13.3 %), both in the 800 mg dose
group. No dose-limiting toxicity (DLT) was observed in the 400 mg group. The
maximum tolerated dose of matuzumab was not reached. The best confirmed overall
response rate was 26.7 %.
CONCLUSION: Matuzumab, in combination with PLF, demonstrated an acceptable
safety profile with modest anti-tumor activity.
DOI: 10.1007/s10637-012-9848-0
PMID: 22763610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23166019 | 1. Genes Dev. 2012 Dec 1;26(23):2604-20. doi: 10.1101/gad.201327.112. Epub 2012
Nov 19.
Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila
homolog of mammalian Mll3/Mll4.
Herz HM(1), Mohan M, Garruss AS, Liang K, Takahashi YH, Mickey K, Voets O,
Verrijzer CP, Shilatifard A.
Author information:
(1)Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3
on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the
body of actively transcribed genes and on enhancers. Although in yeast all H3K4
methylation patterns, including H3K4me1, are implemented by Set1/COMPASS
(complex of proteins associated with Set1), there are three classes of
COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers:
dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the
Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function
as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results
in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays
with the cut wing margin enhancer implied a functional role for Trr in
enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is
required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles
the histone modification patterns described for enhancers. Furthermore, studies
in the mammalian system suggested a role for the Trr homolog Mll3 in similar
processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing
a unique subunit, the H3K27 demethylase UTX, we propose a model in which the
H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX
cooperate to regulate the transition from inactive/poised to active enhancers.
DOI: 10.1101/gad.201327.112
PMCID: PMC3521626
PMID: 23166019 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26569311 | 1. Genes (Basel). 2015 Nov 9;6(4):1183-200. doi: 10.3390/genes6041183.
Super Enhancers in Cancers, Complex Disease, and Developmental Disorders.
Niederriter AR(1), Varshney A(2), Parker SC(3)(4), Martin DM(5)(6)(7).
Author information:
(1)Medical Scientist Training Program, Medical School, University of Michigan,
Ann Arbor, MI 48109, USA. [email protected].
(2)Department of Human Genetics, Medical School, University of Michigan, Ann
Arbor, MI 48109, USA. [email protected].
(3)Department of Human Genetics, Medical School, University of Michigan, Ann
Arbor, MI 48109, USA. [email protected].
(4)Department of Computational Medicine and Bioinformatics, Medical School,
University of Michigan, Ann Arbor, MI 48109, USA. [email protected].
(5)Medical Scientist Training Program, Medical School, University of Michigan,
Ann Arbor, MI 48109, USA. [email protected].
(6)Department of Human Genetics, Medical School, University of Michigan, Ann
Arbor, MI 48109, USA. [email protected].
(7)Department of Pediatrics and Communicable Diseases, Medical School,
University of Michigan, Ann Arbor, MI 48109, USA. [email protected].
Recently, unique areas of transcriptional regulation termed super-enhancers have
been identified and implicated in human disease. Defined by their magnitude of
size, transcription factor density, and binding of transcriptional machinery,
super-enhancers have been associated with genes driving cell differentiation.
While their functions are not completely understood, it is clear that these
regions driving high-level transcription are susceptible to perturbation, and
trait-associated single nucleotide polymorphisms (SNPs) occur within
super-enhancers of disease-relevant cell types. Here we review evidence for
super-enhancer involvement in cancers, complex diseases, and developmental
disorders and discuss interactions between super-enhancers and
cofactors/chromatin regulators.
DOI: 10.3390/genes6041183
PMCID: PMC4690034
PMID: 26569311 |
http://www.ncbi.nlm.nih.gov/pubmed/19276157 | 1. Mol Cancer Ther. 2009 Mar;8(3):481-9. doi: 10.1158/1535-7163.MCT-08-1068. Epub
2009 Mar 10.
Molecular determinants of response to matuzumab in combination with paclitaxel
for patients with advanced non-small cell lung cancer.
Schittenhelm MM(1), Kollmannsberger C, Oechsle K, Harlow A, Morich J, Honecker
F, Kurek R, Störkel S, Kanz L, Corless CL, Wong KK, Bokemeyer C, Heinrich MC.
Author information:
(1)University Hospital Tübingen, Department of Hematology, Oncology,
Rheumatology, Immunology and Pulmonology, Otfried-Müller-Strasse 10, 72074
Tübingen, Germany. [email protected]
Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be
effective in patients with non-small cell lung cancer (NSCLC) that express EGFR.
We recently published a phase I study of weekly matuzumab plus paclitaxel. This
therapy was well tolerated and showed clinical responses in the majority of
patients. Although matuzumab displays potent antitumor activity in some
patients, not all patients respond well to treatment. Whether dysregulation of
EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown.
We sought to determine molecular predictive factors for therapy response in a
phase I/II study patient cohort treated with matuzumab+/-paclitaxel.
Twenty-three cases [including one complete response (CR), three partial
responses (PR), 10 stable diseases (SD)] were screened using
immunohistochemistry (IHC), fluorescence in situ hybridization (FISH),
PCR/sequencing and denaturing wave high performance liquid chromatography
(D-HPLC) for expression, amplification, and mutation status of EGFR and
downstream signaling pathways. All patients with PR or CR displayed an either
high overall or single-cell EGFR expression in the majority of cells. In
addition, all of the moderate responders, who achieved SD after at least two
cycles of therapy, showed diffuse EGFR expression rates and/or strong
single-cell EGFR expression. In contrast, 44% of the nonresponders showed low
overall or single-cell EGFR expression levels. No low-expressing EGFR cases were
present within the responder group. In addition, among patients with a
gain-of-function mutation in KRAS primary therapy failure and/or short responses
to therapy were observed. Our data suggest that EGFR expression and KRAS
mutation status is predictive for clinical response to matuzumab +/- paclitaxel
in patients with advanced NSCLC.
DOI: 10.1158/1535-7163.MCT-08-1068
PMID: 19276157 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10649815 | 1. J Reprod Med. 1999 Dec;44(12 Suppl):1085-90.
Clinical presentation of hyperprolactinemia.
Luciano AA(1).
Author information:
(1)Department of Obstetrics and Gynecology, University of Connecticut School of
Medicine, USA.
Prolactin is a polypeptide hormone essential for lactation. Its production in
the lactotroph cells of the anterior pituitary is regulated primarily by the
inhibitory action of hypothalamic dopamine. Hyperprolactinemia is the most
common endocrine disorder of the hypothalamic-pituitary axis, occurring mostly
in women and presenting most commonly with amenorrhea and galactorrhea. Causes
of hyperprolactinemia include physiologic, pharmacologic and pathologic factors;
pituitary adenoma is a common pathologic cause. Women may present with decreased
libido, infertility, oligomenorrhea/amenorrhea and galactorrhea. Men may present
with decreased libido, infertility, gynecomastia or impotence. In the absence of
an identifiable and treatable underlying cause, hyperprolactinemia is generally
treated with dopamine agonist medications.
PMID: 10649815 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23582322 | 1. Cell. 2013 Apr 11;153(2):307-19. doi: 10.1016/j.cell.2013.03.035.
Master transcription factors and mediator establish super-enhancers at key cell
identity genes.
Whyte WA(1), Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI,
Young RA.
Author information:
(1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
MA 02142, USA.
Comment in
Nat Rev Genet. 2013 Jun;14(6):367. doi: 10.1038/nrg3496.
Master transcription factors Oct4, Sox2, and Nanog bind enhancer elements and
recruit Mediator to activate much of the gene expression program of pluripotent
embryonic stem cells (ESCs). We report here that the ESC master transcription
factors form unusual enhancer domains at most genes that control the pluripotent
state. These domains, which we call super-enhancers, consist of clusters of
enhancers that are densely occupied by the master regulators and Mediator.
Super-enhancers differ from typical enhancers in size, transcription factor
density and content, ability to activate transcription, and sensitivity to
perturbation. Reduced levels of Oct4 or Mediator cause preferential loss of
expression of super-enhancer-associated genes relative to other genes,
suggesting how changes in gene expression programs might be accomplished during
development. In other more differentiated cells, super-enhancers containing
cell-type-specific master transcription factors are also found at genes that
define cell identity. Super-enhancers thus play key roles in the control of
mammalian cell identity.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2013.03.035
PMCID: PMC3653129
PMID: 23582322 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2190528 | 1. Anticancer Res. 1990 Mar-Apr;10(2B):505-11.
Dominant inheritance in human cancer.
Müller H(1).
Author information:
(1)Department of Research, University Clinics, Kantonsspital, Basel,
Switzerland.
Familial aggregations of defined malignancies are of great importance for
determining the genetic factors involved, as has been demonstrated for familial
and sporadic retinoblastoma. In nearly all organs, neoplasms occur that are
inherited similar to familial retinoblastoma (Rb). For example, more than 5% of
all women suffering from breast cancer belong to breast cancer families in which
the occurrence of the malignancy suggests an autosomal dominant pattern of
inheritance. Familial colon cancer is associated with several well-known
autosomal dominantly inherited polyposis syndromes, and also other
susceptibilities without obvious clinical features. Site-specific cancers are
often accompanied by other malignancies. In addition, there seem to be
predispositions to a wider range of different, but well-defined neoplasms: e.g.,
adenocarcinomatosis of the colon and the endometrium, or the Li-Fraumeni/SBLA
syndrome. The latter shows a spectrum of sarcoma, brain tumours, breast cancer,
leukaemias, lung and adenocortical cancer. The genes leading to these types of
dominantly inherited predispositions appear to be the tentatively so-called
tumour suppressor genes, for which the Rb gene serves as a model. It manifests
itself recessively on the level of the individual cell, which means both alleles
must be deleted or inactivated before a retinoblast develops into a neoplastic
cell. Clinical, epidemiological and molecular genetic studies have yet to
establish whether the Rb model can be extended to all other forms of dominantly
inherited human cancers.
PMID: 2190528 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16857825 | 1. Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4441s-4445s. doi:
10.1158/1078-0432.CCR-06-0286.
Epidermal growth factor receptor inhibitors in development for the treatment of
non-small cell lung cancer.
Heymach JV(1), Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R.
Author information:
(1)Department of Thoracic/Head and Neck Oncology, University of Texas M.D.
Anderson Cancer Center, Houston, Texas 77030-4009, USA. [email protected]
The epidermal growth factor receptor (EGFR) inhibitors erlotinib, gefitinib, and
cetuximab have undergone extensive clinical testing and have established
clinical activity in non-small cell lung cancer and other types of solid tumors.
A number of newer inhibitors are currently in clinical development with
different spectra of activity or mechanisms of receptor inhibition. These
include monoclonal antibodies, such as panitumumab and matuzumab; dual
inhibitors of EGFR and vascular endothelial growth factor receptor, such as
ZD6474 and AEE788; inhibitors of multiple EGFR family members, such as
lapatinib; and irreversible inhibitors, such as canertinib and HKI272.
Preclinical studies suggest that several of these agents may have activity in
tumors refractory to erlotinib or gefitinib. Among these agents, ZD6474 has
undergone the most extensive clinical testing. The antitumor activity of ZD6474
in these two randomized phase II clinical trials in patients with non-small cell
lung cancer was felt to be sufficiently promising to warrant phase III clinical
testing. Several of the other EGFR inhibitors are also undergoing advanced
clinical testing, either alone or in combination with other agents. EGFR has now
been validated as a clinically relevant target, and several different types of
agents inhibiting this receptor are currently in development. Future research
will be needed to elucidate the role of these agents in patients with EGFR
inhibitor-naive and EGFR inhibitor-refractory disease, to define the molecular
characteristics that predict response, and to determine whether these drugs
should be used in combination with other targeted agents or chemotherapy.
DOI: 10.1158/1078-0432.CCR-06-0286
PMID: 16857825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9302689 | 1. Mol Med Today. 1997 Sep;3(9):390-5. doi: 10.1016/S1357-4310(97)01105-2.
The Li-Fraumeni syndrome: an inherited susceptibility to cancer.
Evans SC(1), Lozano G.
Author information:
(1)Dept. of Molecular Genetics, University of Texas M.D. Anderson Cancer Center,
Houston 77030, USA. [email protected]
The Li-Fraumeni syndrome is a rare autosomal-dominant disease whose hallmark is
a predisposition to a wide range of cancers among members of a family. Many of
these families have a germline mutation within the tumor suppressor gene TP53,
which encodes the p53 protein. The inheritance of a mutant TP53 allele results
in a 25-fold increase in the chance of developing cancer by 50 years of age,
compared with the general population. TP53 mutations are also very common in the
development of somatic tumors. This article reviews the biological and
biochemical role of p53 in the susceptibility to cancer in Li-Fraumeni syndrome.
DOI: 10.1016/S1357-4310(97)01105-2
PMID: 9302689 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24282181 | 1. J Child Neurol. 2014 Dec;29(12):NP168-70. doi: 10.1177/0883073813509120. Epub
2013 Nov 25.
Mowat-Wilson syndrome: deafness in the first Egyptian case who was conceived by
intracytoplasmic sperm injection.
Abdalla EM(1), Zayed LH(2).
Author information:
(1)Department of Human Genetics, Medical Research Institute, Alexandria
University, Alexandria, Egypt [email protected].
(2)Department of Obstetrics and Gynecology, Alexandria Faculty of Medicine,
Alexandria, Egypt.
Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or
deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome
is characterized by typical facial features, moderate-to-severe mental
retardation, epilepsy and variable congenital malformations, including
Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of
the corpus callosum, and eye defects. The prevalence of Mowat-Wilson syndrome is
currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed,
particularly in patients without Hirschsprung disease. We report here the first
Egyptian case of Mowat-Wilson syndrome who was conceived by intracytoplasmic
sperm injection. The patient manifested bilateral sensorineural hearing loss--a
new feature not previously reported in cases of Mowat-Wilson syndrome. This
report describes the first Egyptian patient of Mowat-Wilson syndrome who was
conceived after intracytoplasmic sperm injection, and provides a new evidence
for the inclusion of deafness among the congenital defects of the syndrome.
© The Author(s) 2013.
DOI: 10.1177/0883073813509120
PMID: 24282181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17420989 | 1. Ann Neurol. 2007 May;61(5):396-402. doi: 10.1002/ana.21127.
Future of neuroprotection for acute stroke: in the aftermath of the SAINT
trials.
Savitz SI(1), Fisher M.
Author information:
(1)Department of Neurology, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA 02215, USA. [email protected]
Comment in
Ann Neurol. 2007 Dec;62(6):677-8; author reply 678. doi: 10.1002/ana.21210.
The concept of neuroprotective therapy for acute ischemic stroke to salvage
tissue at risk and improve functional outcome is based on sound scientific
principles and extensive preclinical animal studies demonstrating efficacy. The
failure of most neuroprotective drugs in clinical trials has been due to
inadequate preclinical testing and flawed clinical development programs. The
Stroke Therapy Academic Industry Roundtable (STAIR) group has outlined rational
approaches to preclinical and clinical studies. The positive results from the
first Stroke-Acute-Ischaemic-NXY-Treatment (SAINT-I) trial of the free-radical
spin-trap drug, NXY-059, which followed many of the STAIR guidelines,
reinvigorated enthusiasm in neuroprotection, but the SAINT-II trial did not
replicate the positive effect on the same primary prespecified outcome measure.
This has led to concerns about the future of neuroprotection as a therapeutic
strategy for acute ischemic stroke. We discuss new suggestions to bridge the
chasm between preclinical animal modeling and acute human stroke trials to
potentially enhance the future assessment of novel neuroprotective drugs.
DOI: 10.1002/ana.21127
PMID: 17420989 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12531390 | 1. DNA Repair (Amst). 2003 Feb 3;2(2):199-210. doi:
10.1016/s1568-7864(02)00198-2.
Repair of the mutagenic DNA oxidation product, 5-formyluracil.
Liu P(1), Burdzy A, Sowers LC.
Author information:
(1)Department of Biochemistry and Microbiology, School of Medicine, Loma Linda
University, Loma Linda, CA 92350, USA.
The oxidation of the thymine methyl group can generate 5-formyluracil (FoU).
Template FoU residues are known to miscode, generating base substitution
mutations. The repair of the FoU lesion is therefore important in minimizing
mutations induced by DNA oxidation. We have studied the repair of FoU in
synthetic oligonucleotides when paired with A and G. In E. coli cell extract,
the repair of FoU is four orders of magnitude lower than the repair of U and is
similar for both FoU:A and FoU:G base pairs. In HeLa nuclear extract, the repair
of FoU:A is similarly four orders of magnitude lower than the repair of uracil,
although the FoU:G lesion is repaired 10 times more efficiently than FoU:A. The
FoU:G lesion is shown to be repaired by E. coli mismatch uracil DNA glycosylase
(Mug), thermophile mismatch thymine DNA glycosylase (Tdg), mouse mismatch
thymine DNA glycosylase (mTDG) and human methyl-CpG-binding thymine DNA
glycosylase (MBD4), whereas the FoU:A lesion is repaired only by Mug and mTDG.
The repair of FoU relative to the other pyrimidines examined here in human cell
extract differs from the substrate preferences of the known glycosylases,
suggesting that additional, and as yet unidentified glycosylases exist in human
cells to repair the FoU lesion. Indeed, as observed in HeLa nuclear extract, the
repair of mispaired FoU derived from misincorporation of dGMP across from
template FoU could promote rather than minimize mutagenesis. The pathways by
which this important lesion is repaired in human cells are as yet unexplained,
and are likely to be complex.
DOI: 10.1016/s1568-7864(02)00198-2
PMID: 12531390 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25110833 | 1. Free Radic Biol Med. 2014 Nov;76:53-60. doi:
10.1016/j.freeradbiomed.2014.07.042. Epub 2014 Aug 10.
Molecular speciation and dynamics of oxidized triacylglycerols in lipid
droplets: Mass spectrometry and coarse-grained simulations.
Mohammadyani D(1), Tyurin VA(2), O'Brien M(3), Sadovsky Y(3), Gabrilovich DI(4),
Klein-Seetharaman J(5), Kagan VE(6).
Author information:
(1)Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA 15219, USA; Department of Bioengineering, University
of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and
Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
(2)Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant
Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
(3)Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA
15219, USA.
(4)The Wistar Institute, Philadelphia, PA 19104, USA.
(5)Division of Metabolic and Vascular Health, Medical School, University of
Warwick, Coventry CV4 7AL, UK.
(6)Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant
Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address:
[email protected].
Lipid droplets (LDs) are ubiquitous and physiologically active organelles
regulating storage and mobilization of lipids in response to metabolic demands.
Among the constituent LD neutral lipids, such as triacylglycerols, cholesterol
esters, and free fatty acids, oxidizable polyunsaturated molecular species may
be quite abundant, yet the structural and functional roles of their oxidation
products have not been studied. Our previous work documented the presence of
these peroxidized species in LDs. Assuming that hydrophilic oxygen-containing
functionalities may markedly change the hydrophobic/hydrophilic molecular
balance, here we utilized computational modeling to test the hypothesis that
lipid peroxidation causes redistribution of lipids between the highly
hydrophobic core and the polar surface (phospho)lipid monolayer-the area
enriched with integrated enzymatic machinery. Using quantitative liquid
chromatography/mass spectrometry, we characterized molecular speciation of
oxTAGs in LDs of dendritic cells in cancer and hypoxic trophoblasts cells as two
cellular models associated with dyslipidemia. Among the many types of oxidized
lipids identified, we found that oxidatively truncated forms and hydroxyl
derivatives of TAGs were the prevailing oxidized lipid species in LDs in both
cell types. Using coarse-grained molecular dynamics (CG-MD) simulations we
established that lipid oxidation changed their partitioning whereby oxidized
lipids migrated into the outer monolayer of the LD, where they can affect
essential metabolic pathways and undergo conversions, possibly leading to the
formation of oxygenated lipid mediators.
Published by Elsevier Inc.
DOI: 10.1016/j.freeradbiomed.2014.07.042
PMCID: PMC4276254
PMID: 25110833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16533873 | 1. Ann Oncol. 2006 Jun;17(6):1007-13. doi: 10.1093/annonc/mdl042. Epub 2006 Mar
13.
A phase I study of the humanized monoclonal anti-epidermal growth factor
receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with paclitaxel in
patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC).
Kollmannsberger C(1), Schittenhelm M, Honecker F, Tillner J, Weber D, Oechsle K,
Kanz L, Bokemeyer C.
Author information:
(1)Department of Hematology/Oncology, University of Tuebingen, Germany.
BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in 80%-90%
of non-small-cell lung cancer (NSCLC). Matuzumab, a humanized immunoglobulin
G(1) (IgG(1)) anti-EGFR monoclonal antibody, blocks activation of EGFR.
Paclitaxel and EGFR inhibitors have additive antitumour effects in vitro. This
phase I study assessed the tolerability, pharmacokinetics and efficacy of the
combination of matuzumab and paclitaxel in patients with advanced NSCLC.
MATERIALS AND METHODS: Eighteen chemotherapy-naïve (n = 9) or pretreated (n = 9)
patients with stage IIIB or IV EGFR-positive NSCLC received weekly doses of
matuzumab (100, 200, 400 or 800 mg) followed by paclitaxel 175 mg/m(2) every 3
weeks. Toxicity was evaluated weekly and pharmacokinetics were measured during
cycles 1 and 2.
RESULTS: The maximum planned matuzumab dose of 800 mg was achieved without
reaching the maximum tolerated dose. Grade 4 neutropenia occurred in one of
three patients at 800 mg but resolved within 1 week; five additional patients
treated with 800 mg had no dose-limiting toxicity (DLT). Grade 1/2 acneiform
skin rash in 14 patients was the most frequent matuzumab-related side-effect.
There were no higher-grade adverse events. Grade 2 toxicities included pruritus
(n = 2), bronchospasm (n = 1), fissures (n = 1), abdominal pain (n = 1) and hot
flushes (n = 1). Paclitaxel was discontinued in four patients due to allergic
reactions. Coadministration of paclitaxel did not alter matuzumab
pharmacokinetics. Responses occurred in four of 18 patients and included one
complete response.
CONCLUSIONS: Matuzumab doses up to 800 mg weekly with paclitaxel 175 mg/m(2)
every 3 weeks are well tolerated, with no apparent drug interactions and with
evidence of antitumor activity.
DOI: 10.1093/annonc/mdl042
PMID: 16533873 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20075382 | 1. Dis Model Mech. 2010 Jan-Feb;3(1-2):45-56. doi: 10.1242/dmm.003749.
Genetic modeling of Li-Fraumeni syndrome in zebrafish.
Parant JM(1), George SA, Holden JA, Yost HJ.
Author information:
(1)Department of Neurobiology, University of Utah School of Medicine, Salt Lake
City, UT 84112, USA.
Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human
familial cancer predisposition. Although a key role for the tumor suppressor p53
has been implicated in LFS, the genetic and cellular mechanisms underpinning
this disease remain unknown. Therefore, modeling LFS in a vertebrate system that
is accessible to both large-scale genetic screens and in vivo cell biological
studies will facilitate the in vivo dissection of disease mechanisms, help
identify candidate genes, and spur the discovery of therapeutic compounds. Here,
we describe a forward genetic screen in zebrafish embryos that was used to
identify LFS candidate genes, which yielded a p53 mutant (p53(I166T)) that as an
adult develops tumors, predominantly sarcomas, with 100% penetrance. As in
humans with LFS, tumors arise in heterozygotes and display loss of
heterozygosity (LOH). This report of LOH indicates that Knudson's two-hit
hypothesis, a hallmark of human autosomal dominant cancer syndromes, can be
modeled in zebrafish. Furthermore, as with some LFS mutations, the zebrafish
p53(I166T) allele is a loss-of-function allele with dominant-negative activity
in vivo. Additionally, we demonstrate that the p53 regulatory pathway, including
Mdm2 regulation, is evolutionarily conserved in zebrafish, providing a bona fide
biological context in which to systematically uncover novel modifier genes and
therapeutic agents for human LFS.
DOI: 10.1242/dmm.003749
PMCID: PMC2806900
PMID: 20075382 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22807624 | 1. Biologics. 2012;6:137-46. doi: 10.2147/BTT.S23917. Epub 2012 Jun 20.
Metastatic gastric cancer - focus on targeted therapies.
Meza-Junco J(1), Sawyer MB.
Author information:
(1)Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
Gastric cancer (GC) is currently the second leading cause of cancer death
worldwide; unfortunately, most patients will present with locally advanced or
metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy,
and radiotherapy, prognosis remains poor. A better understanding of GC biology
and signaling pathways is expected to improve GC therapy, and the integration of
targeted therapies has recently become possible and appears to be promising.
This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as
other epidermal growth factor receptor antagonists such as cetuximab, panitumub,
matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target
angiogenesis pathways are also under investigation, particulary bevacizumab,
ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in
preclinical or early clinical development include mTOR inhibitors, anti c-MET,
polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock
proteins, and small molecules targeting Hedgehog signaling.
DOI: 10.2147/BTT.S23917
PMCID: PMC3395896
PMID: 22807624 |
http://www.ncbi.nlm.nih.gov/pubmed/22832803 | 1. Invest New Drugs. 2013 Jun;31(3):661-8. doi: 10.1007/s10637-012-9856-0. Epub
2012 Jul 26.
A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in
patients with EGFR-expressing advanced non-small cell lung cancer.
Hartmann JT(1), Kollmannsberger C, Cascorbi I, Mayer F, Schittenhelm MM, Heeger
S, Bokemeyer C.
Author information:
(1)Department of Hematology/Oncology, University Hospital Schleswig-Holstein,
Christian-Albrechts-University Cancer Center North, Arnold-Heller-Strasse 3,
24105, Kiel, Germany. [email protected]
Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study
investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in
combination with paclitaxel in patients with EGFR-expressing advanced non-small
cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored
in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a
modified Fibonacci scheme according to the incidence of dose-limiting toxicity
(DLT) over the first two cycles. DLT was assessed in patients who completed the
first two treatment cycles or who stopped treatment because of a DLT during
those cycles. Patients with non-progressive disease could then continue to
receive study treatment for up to 6 months. The safety population comprised 44
patients, with DLT evaluable in 33. The maximum tolerated dose was not reached,
with only one DLT reported at the 1,600 mg 3-weekly dose level. The most
frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and
neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after
escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %)
patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab
combined with paclitaxel was generally well tolerated in patients with advanced
NSCLC. There was some evidence of anticancer activity in relation to the
matuzumab 800 mg weekly dose.
DOI: 10.1007/s10637-012-9856-0
PMID: 22832803 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23300028 | 1. Target Oncol. 2013 Mar;8(1):47-53. doi: 10.1007/s11523-012-0244-7. Epub 2013
Jan 9.
EGFR-directed monoclonal antibodies in non-small cell lung cancer.
Pirker R(1).
Author information:
(1)Department of Medicine I, Medical University of Vienna, Währinger Gürtel
18-20, 1090, Vienna, Austria. [email protected]
Several monoclonal antibodies directed against the epidermal growth factor
receptor (EGFR) have been evaluated in patients with non-small cell lung cancer
(NSCLC). Cetuximab, a chimeric monoclonal antibody, has been studied in
combination with first-line chemotherapy in phase II and two phase III trials in
patients with advanced NSCLC. The phase III FLEX trial demonstrated an increase
in survival for cisplatin/vinorelbine plus cetuximab compared to chemotherapy
alone in patients with advanced EGFR-expressing NSCLC. Cetuximab added to
carboplatin/paclitaxel failed to improve progression-free survival in the BMS099
phase III trial. However, a meta-analysis of four randomized trials confirmed a
significant survival benefit for platinum-based chemotherapy plus cetuximab
compared to chemotherapy alone. High EGFR expression of tumor cells was then
shown to predict the benefit of cetuximab, whereas KRAS mutations and EGFR
fluorescent in situ hybridization analysis were without predictive value.
Matuzumab and panitumumab have also been studied in phase II trials.
Necitumumab, a fully human monoclonal antibody, is currently evaluated in
combination with chemotherapy in two phase III trials in patients with advanced
NSCLC. Cetuximab is also studied in combination with chemoradiotherapy in
patients with locally advanced NSCLC.
DOI: 10.1007/s11523-012-0244-7
PMID: 23300028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16622465 | 1. Br J Cancer. 2006 May 8;94(9):1293-9. doi: 10.1038/sj.bjc.6603083.
Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD
72000) combined with gemcitabine in advanced pancreatic cancer.
Graeven U(1), Kremer B, Südhoff T, Killing B, Rojo F, Weber D, Tillner J, Unal
C, Schmiegel W.
Author information:
(1)Department of Medicine, Ruhr University Bochum (Knappschaftskrankenhaus), In
der Schornau 23-25, Bochum 44892, and Department of General Surgery and Thoracic
Surgery, University Hospital of Schleswig-Holstein, Kiel, Germany.
[email protected]
The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody
matuzumab (formerly EMD 72000) is active against pancreatic cancer in
preclinical studies. This phase I study assessed the safety and potential
benefit of combined treatment with matuzumab and standard-dose gemcitabine.
Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients
(n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly,
or 800 mg weekly) and gemcitabine (1000 mg m-2 weekly in weeks 1-3 of each
4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters,
and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe
treatment-related toxicities were limited to grade 3 neutropenia (n=3),
leucopenia (n=1), and decreased white blood cell count (n=1). Common study
drug-related adverse events were skin toxicities (grade 2=6, grade 1=7) and
fever (grade 1=4). Matuzumab inhibited phosphorylated EGFR and affected
receptor-dependent signalling and transduction; effects were seen even in the
lowest-dose group. Pharmacokinetic data were consistent with results of
matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight
of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in
the group receiving 800 mg weekly. Matuzumab in biologically effective doses
with standard gemcitabine therapy appears well tolerated. The combination is
feasible and may have enhanced activity.
DOI: 10.1038/sj.bjc.6603083
PMCID: PMC2361405
PMID: 16622465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20497967 | 1. Ann Oncol. 2010 Nov;21(11):2213-2219. doi: 10.1093/annonc/mdq247. Epub 2010
May 23.
Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with
epirubicin, cisplatin and capecitabine alone as first-line treatment in patients
with advanced oesophago-gastric cancer: a randomised, multicentre open-label
phase II study.
Rao S(1), Starling N(1), Cunningham D(2), Sumpter K(3), Gilligan D(4),
Ruhstaller T(5), Valladares-Ayerbes M(6), Wilke H(7), Archer C(8), Kurek R(9),
Beadman C(9), Oates J(1).
Author information:
(1)Gastrointestinal Unit, Royal Marsden Hospital, London and Surrey, UK.
(2)Gastrointestinal Unit, Royal Marsden Hospital, London and Surrey, UK.
Electronic address: [email protected].
(3)Oncology Department, Newcastle General Hospital, Newcastle, UK.
(4)Oncology Department, Addenbrooke's NHS Trust, Cambridge, UK.
(5)Department of Haematology and Oncology, St Gallen, Switzerland.
(6)Department of Medical Oncology, Complejo Hospitalario Juan Canalejo, A
Coruña, Spain.
(7)Oncology Department, Kliniken Essen-Mitte, Essen, Germany.
(8)Oncology Department, St Mary's Hospital, Portsmouth, UK.
(9)Gastrointestinal Oncology, Merck Serono, Darmstadt, Germany.
BACKGROUND: Clinical data showed promising antitumour activity with feasible
tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX)
chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to
evaluate the efficacy of matuzumab plus ECX versus ECX alone.
PATIENTS AND METHODS: In this multicentre, randomised open-label phase II study,
72 patients with metastatic OG cancer were randomly assigned to either 800 mg
matuzumab weekly plus epirubicin 50 mg/m², cisplatin 60 mg/m² on day 1 and
capecitabine 1250 mg/m² daily in a 21-day cycle (ECX) or the same ECX regimen
alone. The primary end point was objective response. Secondary end points
included progression-free survival (PFS), overall survival (OS), quality of
life, safety and tolerability.
RESULTS: Following random assignment, 35 patients (median age 59 years) received
ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of
matuzumab to ECX did not improve objective response: 31% for ECX/matuzumab [95%
confidence interval (CI) 17-49] compared with 58% for the ECX arm (95% CI 41-74)
P = 0.994 (one sided). There was no significant difference in median PFS: 4.8
months (95% CI 2.9-8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4-8.5) for
ECX, or in median OS: 9.4 months (95% CI 7.5-16.2), compared with 12.2 months
(95% CI 9.8-13.8 months). Grade 3/4 treatment-related toxicity was observed in
27 and 25 patients in the ECX/matuzumab and ECX groups, respectively.
CONCLUSION: Matuzumab 800 mg weekly combined with ECX chemotherapy does not
increase response or survival for patients with advanced OG cancer. Therefore,
ECX/matuzumab should not be examined further in phase III trials.
DOI: 10.1093/annonc/mdq247
PMID: 20497967 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22258451 | 1. Cancer Res. 2012 Mar 1;72(5):1149-56. doi: 10.1158/0008-5472.CAN-11-2904. Epub
2012 Jan 18.
ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair
pathway.
Shigechi T(1), Tomida J, Sato K, Kobayashi M, Eykelenboom JK, Pessina F, Zhang
Y, Uchida E, Ishiai M, Lowndes NF, Yamamoto K, Kurumizaka H, Maehara Y, Takata
M.
Author information:
(1)Laboratory of DNA Damage Signaling, Department of Late Effects Studies,
Radiation Biology Center, Kyoto University, Kyoto, Japan.
ATR kinase activates the S-phase checkpoint when replication forks stall at
sites of DNA damage. This event also causes phosphorylation of the Fanconi
anemia (FA) protein FANCI, triggering its monoubiquitination of the key DNA
repair factor FANCD2 by the FA core E3 ligase complex, thereby promoting this
central pathway of DNA repair which permits replication to be restarted.
However, the interplay between ATR and the FA pathway has been unclear. In this
study, we present evidence that their action is directly linked, gaining
insights into this relationship in a DT40 mutant cell line that is conditionally
deficient in the critical ATR-binding partner protein ATRIP. Using this system,
we showed that ATRIP was crucial for DNA damage-induced FANCD2
monoubiquitination and FANCI phosphorylation. ATR kinase phosphorylated
recombinant FANCI protein in vitro, which was facilitated by the presence of
FANCD2. Mechanistic investigations revealed that the RPA region but not the
TopBP1 region of ATRIP was required for FANCD2 monoubiquitination, whereas Chk1
phosphorylation relied upon both domains. Together, our findings identify ATR as
the kinase responsible for activating the FA pathway of DNA repair.
DOI: 10.1158/0008-5472.CAN-11-2904
PMID: 22258451 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22727480 | 1. Psychoneuroendocrinology. 2013 Jan;38(1):145-54. doi:
10.1016/j.psyneuen.2012.05.011. Epub 2012 Jun 21.
Chronic systemic administration of serotonergic ligands flibanserin and
8-OH-DPAT enhance HPA axis responses to restraint in female marmosets.
Aubert Y(1), Bohl MA, Lange JR, Diol NR, Allers KA, Sommer B, Datson NA, Abbott
DH.
Author information:
(1)Wisconsin National Primate Research Center, University of Wisconsin-Madison,
WI, USA. [email protected]
BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A)
antagonist, has been shown to increase sexual desire and reduce distress in
women with Hypoactive Sexual Desire Disorder (HSDD). In marmoset monkeys,
flibanserin has demonstrated pro-social effects on male-female pairmates, while
the classic 5-HT(1A) agonist 8-OH-DPAT suppresses female sexual behavior and
increases aggressive interactions between pairmates. Activation of 5-HT(1A) and
5-HT(2A) receptors is known to stimulate the hypothalamic-pituitary-adrenal
(HPA) axis. This study aims to characterize the effects of repeated flibanserin
and 8-OH-DPAT administration on the marmoset HPA axis and to elucidate endocrine
correlates of altered marmoset pair behavior.
METHODS: Adrenocorticotropic hormone (ACTH) and cortisol were examined at
baseline and during 5-HT(1A) agonist and restraint challenges in 8 female
marmoset monkeys receiving daily flibanserin (15mg/kg) and an additional 8
female marmosets receiving 8-OH-DPAT (0.1mg/kg) for 15-16weeks. Corresponding
vehicle treatments were administered in a counterbalanced, within-subject
design. All females were housed in stable male-female pairs. Treatment-induced
changes in ACTH and cortisol levels were correlated with previously assessed
marmoset pair behavior.
RESULTS: While morning basal cortisol levels and HPA responses to a 5-HT(1A)
agonist challenge were not altered by chronic flibanserin or 8-OH-DPAT, both
treatments increased the responsiveness of the marmoset HPA axis to restraint.
Enhanced ACTH responses to restraint correlated with reduced sexual receptivity
and increased aggression in 8-OH-DPAT-, but not in flibanserin-treated female
marmosets.
CONCLUSIONS: Unaltered HPA responses to a 5-HT(1A) agonist challenge after
chronic flibanserin and 8-OH-DPAT treatments indicate little or no
de-sensitization of the HPA axis to repeated 5-HT(1A) manipulation. Chronic
8-OH-DPAT, but not flibanserin, leads to aggravated ACTH responses to stress
that may contribute to anti-sexual and anti-social behavior between
8-OH-DPAT-treated females and their male pairmates. Despite similar flibanserin
and 8-OH-DPAT induced ACTH responses to restraint stress, flibanserin-treated
females show unchanged cortisol profiles. This is possibly due to flibanserin's
regional selectivity in 5-HT(1A) activation and concurrent 5-HT(2A) inhibition.
The contrasting restraint-related cortisol responses emulate contrasting
behavioral phenotypes of diminished pair-bond of 8-OH-DPAT-treated females
compared to the more affiliative pair-bond of flibanserin-treated females.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.psyneuen.2012.05.011
PMID: 22727480 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7678559 | 1. FASEB J. 1993 Jan;7(1):155-60. doi: 10.1096/fasebj.7.1.7678559.
Mis-splicing yields circular RNA molecules.
Cocquerelle C(1), Mascrez B, Hétuin D, Bailleul B.
Author information:
(1)Unité 124 INSERM, Institut de Recherches sur le Cancer, Lille, France.
We previously identified novel human ets-1 transcripts in which the normal order
of exons is inverted, and demonstrated that although the order of exons is
different than in the genomic DNA, splicing of these exons out of order occurs
in pairs using genuine splice sites (1). Here we determine the structure of
these novel transcripts, showing that they correspond to circular RNA molecules
containing only exons in genomic order. These transcripts are stable molecules,
localized in the cytoplasmic component of the cells. To our knowledge, this is
the first case of circular transcripts being processed from nuclear pre-mRNA in
eukaryotes. This new type of transcript might represent a novel aspect of gene
expression and hold some interesting clues about the splicing mechanism.
DOI: 10.1096/fasebj.7.1.7678559
PMID: 7678559 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17126894 | 1. Gynecol Oncol. 2007 Mar;104(3):727-31. doi: 10.1016/j.ygyno.2006.10.019. Epub
2006 Nov 28.
A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal
antibody, in patients with platinum-resistant ovarian and primary peritoneal
malignancies.
Seiden MV(1), Burris HA, Matulonis U, Hall JB, Armstrong DK, Speyer J, Weber JD,
Muggia F.
Author information:
(1)Massachusetts General Hospital, 100 Blossom Street, Cox 640, Boston, MA
02114, USA. [email protected]
OBJECTIVE: The primary objective of this study was to determine the rate of
response to matuzumab in patients with recurrent, EGFR-positive ovarian, or
primary peritoneal cancer. Secondary end points included safety and
tolerability, time to tumor progression, duration of response, and overall
survival.
METHODS: A multi-institutional single arm phase II trial.
RESULTS: Of 75 women screened for the study, 37 were enrolled and treated.
Median age of the treated patient population was 58 years, and most patients had
more than four prior lines of chemotherapy. Therapy was well tolerated, the most
common toxicities being a constellation of skin toxicities, including rash,
acne, dry skin, and paronychia, as well as headache, fatigue, and diarrhea.
Serious adverse events were very rare but included a single episode of
pancreatitis that may have been drug related. All patients completed therapy,
receiving 1 to 30 infusions of matuzumab. There were no formal responses (RR=0%,
95% CI: 0-9.5%), although 7 patients (21%) were on therapy for more than 3
months with stable disease.
CONCLUSIONS: Matuzumab at the dose and schedule selected is well tolerated. In
this population of very heavily pretreated patients with epithelial ovarian and
primary peritoneal malignancies, there was no evidence of significant clinical
activity when matuzumab was administered as monotherapy.
DOI: 10.1016/j.ygyno.2006.10.019
PMID: 17126894 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3595535 | 1. Endocrinology. 1987 Aug;121(2):650-6. doi: 10.1210/endo-121-2-650.
Comparison of kidney and brown adipose tissue iodothyronine 5'-deiodinases.
Silva JE, Mellen S, Larsen PR.
We have examined the influence of assay conditions on the
6-n-propyl-2-thiouracil (PTU) sensitivity of the iodothyronine 5'-deiodinase in
brown adipose tissue (BAT) from hypothyroid rats. These results were compared
with similar studies of 5'-deiodinase activity in kidney microsomes from
euthyroid animals. Even though BAT microsomes contain largely type II
(PTU-insensitive) deiodinase activity, the 5'-deiodination of T4 can be
inhibited by PTU if the dithiothreitol (DTT) concentration in the assay is
reduced to 5 mM or less. The apparent Ki for PTU of BAT microsomes was 4.3 mM at
5.0 mM DTT and 0.41 mM at 0.5 mM DTT. The kinetics of inhibition were
noncompetitive. With kidney microsomes, PTU inhibition of rT3 5'-deiodination
was both time and enzyme/substrate ratio dependent. For example, using 1
microgram microsomal protein, 2 nM rT3, and 5 mM DTT, the inhibitory effect of
PTU was not maximal until 12 min after PTU addition. At stable reaction
velocities PTU inhibition was uncompetitive, and the Ki was about 1 microM.
Deiodination by kidney microsomes was completely inhibited by 50 microM PTU.
Even though it is possible to inhibit the type II 5'-deiodinase activity with
high concentrations of PTU (in the presence of low DTT concentrations), the
deiodinase in kidney is about 1000-fold more sensitive to PTU. By these criteria
the kidney microsome 5'-deiodinase is type I.
DOI: 10.1210/endo-121-2-650
PMID: 3595535 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12436031 | 1. Curr Opin Pediatr. 2002 Dec;14(6):664-8. doi:
10.1097/00008480-200212000-00002.
Clinical trials of treatments after perinatal asphyxia.
Whitelaw A(1), Thoresen M.
Author information:
(1)Division of Child Health, University of Bristol, Bristol, United Kingdom.
[email protected]
Following critical hypoxia-ischemia during labor and delivery, there is a window
of therapeutic opportunity during hypoxic-ischemic encephalopathy. Meta-analysis
of three randomized trials of prophylactic barbiturate therapy for neonatal
hypoxic-ischemic encephalopathy showed no significant effect on death or
disability. One randomized trial of allopurinol showed short-term benefits but
was too small to test death or disability. No adequate trials of dexamethasone,
calcium channel blockers, or magnesium sulphate have yet been completed, but
pilot studies in infants have shown the cardiovascular risks of magnesium
sulphate and calcium channel blockers. There is considerable evidence from
animal studies that posthypoxic mild hypothermia reduces brain injury. One small
randomized trial of mild hypothermia found no adverse effects but was too small
to examine death or disability. One large randomized trial of selective head
cooling has finished recruitment and a number of large trials of systemic mild
hypothermia are ongoing. As time is critical with post-hypoxic interventions,
the delay involved in obtaining informed parental consent for such trials might
obscure a clinically important therapeutic effect.
DOI: 10.1097/00008480-200212000-00002
PMID: 12436031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15871762 | 1. Clin Colorectal Cancer. 2005 Apr;5 Suppl 1:S19-27.
Epidermal growth factor receptor as a target for chemotherapy.
Vallbohmer D(1), Lenz HJ.
Author information:
(1)Division of Medical Oncology, University of Southern California/Norris
Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033,
USA.
The epidermal growth factor receptor (EGFR) is overexpressed in as many as 77%
of colorectal cancer (CRC) cases. The EGFR is known to be involved in
carcinogenetic processes such as cell proliferation, apoptosis, angiogenesis,
cell motility, and metastasis. Preclinical and clinical studies have shown that
targeting EGFR is a valid strategy for anticancer therapy. Currently, 2 classes
of anti-EGFR agents are in phase II/III clinical development: monoclonal
antibodies and tyrosine kinase (TK) inhibitors. The most established monoclonal
antibody is cetuximab, the only EGFR inhibitor that is currently approved for
use in patients with metastatic CRC. Several clinical studies of cetuximab, as a
single agent or in combination with irinotecan, have shown promising efficacy in
patients with metastatic CRC. Two other monoclonal antibodies, matuzumab (EMD
72000) and panitumumab (ABG-EGF), also have shown activity against
EGFR-expressing CRC but are still in the early stage of clinical development.
The activity of the EGFR TK inhibitors erlotinib and gefitinib have already been
investigated in clinical phase III trials in patients with non-small-lung
cancer, suggesting that sequential rather than concurrent
erlotinib/gefitinib-based treatment provides a benefit in clinical outcome. The
EGFR-targeting agents are reasonably well tolerated and have limited overlapping
toxicities in combination with other cytotoxic drugs. The most common side
effect of anti-EGFR treatment is an acneiform skin rash, which is associated
with the clinical outcome of treatment with monoclonal antibodies and TK
inhibitors. Future clinical studies are needed to establish these EGFR-targeting
agents in anticancer treatment to investigate efficacy of therapies combining
EGFR-targeted agents with other targeting agents and to describe additional
markers determining the clinical outcome of anti-EGFR therapy.
PMID: 15871762 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25894691 | 1. Cell Mol Life Sci. 2015 Jul;72(14):2677-95. doi: 10.1007/s00018-015-1903-5.
Epub 2015 Apr 18.
Lipid droplet dynamics in budding yeast.
Wang CW(1).
Author information:
(1)Institute of Plant and Microbial Biology, Academia Sinica, Nankang, Taipei,
11529, Taiwan, [email protected].
Eukaryotic cells store excess fatty acids as neutral lipids, predominantly
triacylglycerols and sterol esters, in organelles termed lipid droplets (LDs)
that bulge out from the endoplasmic reticulum. LDs are highly dynamic and
contribute to diverse cellular functions. The catabolism of the storage lipids
within LDs is channeled to multiple metabolic pathways, providing molecules for
energy production, membrane building blocks, and lipid signaling. LDs have been
implicated in a number of protein degradation and pathogen infection processes.
LDs may be linked to prevalent human metabolic diseases and have marked
potential for biofuel production. The knowledge accumulated on LDs in recent
years provides a foundation for diverse, and even unexpected, future research.
This review focuses on recent advances in LD research, emphasizing the diverse
physiological roles of LDs in the model system of budding yeast.
DOI: 10.1007/s00018-015-1903-5
PMCID: PMC11113813
PMID: 25894691 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11239186 | 1. Stroke. 2001 Mar;32(3):675-80. doi: 10.1161/01.str.32.3.675.
Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute
stroke.
Lees KR(1), Sharma AK, Barer D, Ford GA, Kostulas V, Cheng YF, Odergren T.
Author information:
(1)University Department of Medicine and Therapeutics, Western Infirmary,
Glasgow, UK.
BACKGROUND AND PURPOSE: Increased free radical formation contributes to the
damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free
radical trapping agent in development for acute stroke. NXY-059 has
neuroprotective efficacy when given 5 hours after onset of transient focal
ischemia in the rat.
METHODS: This was a randomized, double-blind, placebo-controlled, parallel
group, multicenter study that evaluated the safety and tolerability of 2 NXY-059
dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059
was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours
or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations
were monitored. Neurological and functional outcomes were recorded up to 30
days.
RESULTS: One hundred fifty patients were recruited, of whom 147 received study
treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49
higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline
National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious
adverse events occurred in 16%, 23%, and 16% of patients, respectively, with
deaths in 0%, 10%, and 4%, largely following the proportions with primary
intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever
were common but not related to treatment. The mean unbound steady state NXY-059
plasma concentrations were 25 and 45 micromol/L, respectively. Population
pharmacokinetic analysis estimated clearance to be 4.6 L/h.
CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke. The
testing of higher doses in future trials may be justified.
DOI: 10.1161/01.str.32.3.675
PMID: 11239186 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24609083 | 1. PLoS One. 2014 Mar 7;9(6):e90859. doi: 10.1371/journal.pone.0090859.
eCollection 2014.
Circular RNA is expressed across the eukaryotic tree of life.
Wang PL(1), Bao Y(2), Yee MC(2), Barrett SP(3), Hogan GJ(3), Olsen MN(4),
Dinneny JR(2), Brown PO(4), Salzman J(1).
Author information:
(1)Department of Biochemistry, Stanford University School of Medicine, Stanford,
California, United States of America; Stanford Cancer Institute, Stanford
University School of Medicine, Stanford, California, United States of America.
(2)Department of Plant Biology, Carnegie Institution for Science, Stanford,
California, United States of America; Temasek Lifesciences Laboratory, National
University of Singapore, Singapore, Singapore; Department of Biological
Sciences, National University of Singapore, Singapore, Singapore.
(3)Department of Biochemistry, Stanford University School of Medicine, Stanford,
California, United States of America.
(4)Department of Biochemistry, Stanford University School of Medicine, Stanford,
California, United States of America; Howard Hughes Medical Institute, Stanford
University School of Medicine, Stanford, California, United States of America.
Erratum in
PLoS One. 2014;9(4):e95116.
An unexpectedly large fraction of genes in metazoans (human, mouse, zebrafish,
worm, fruit fly) express high levels of circularized RNAs containing canonical
exons. Here we report that circular RNA isoforms are found in diverse species
whose most recent common ancestor existed more than one billion years ago: fungi
(Schizosaccharomyces pombe and Saccharomyces cerevisiae), a plant (Arabidopsis
thaliana), and protists (Plasmodium falciparum and Dictyostelium discoideum).
For all species studied to date, including those in this report, only a small
fraction of the theoretically possible circular RNA isoforms from a given gene
are actually observed. Unlike metazoans, Arabidopsis, D. discoideum, P.
falciparum, S. cerevisiae, and S. pombe have very short introns (∼ 100
nucleotides or shorter), yet they still produce circular RNAs. A minority of
genes in S. pombe and P. falciparum have documented examples of canonical
alternative splicing, making it unlikely that all circular RNAs are by-products
of alternative splicing or 'piggyback' on signals used in alternative RNA
processing. In S. pombe, the relative abundance of circular to linear transcript
isoforms changed in a gene-specific pattern during nitrogen starvation. Circular
RNA may be an ancient, conserved feature of eukaryotic gene expression programs.
DOI: 10.1371/journal.pone.0090859
PMCID: PMC3946582
PMID: 24609083 [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/22709256 | 1. Future Med Chem. 2012 Jun;4(9):1171-207. doi: 10.4155/fmc.12.74.
Potential implication of the chemical properties and bioactivity of nitrone spin
traps for therapeutics.
Villamena FA(1), Das A, Nash KM.
Author information:
(1)Department of Pharmacology, & Davis Heart & Lung Research Institute, College
of Medicine, The Ohio State University, Columbus, OH 43210, USA.
[email protected]
Nitrone therapeutics has been employed in the treatment of oxidative
stress-related diseases such as neurodegeneration, cardiovascular disease and
cancer. The nitrone-based compound NXY-059, which is the first drug to reach
clinical trials for the treatment of acute ischemic stroke, has provided promise
for the development of more robust pharmacological agents. However, the specific
mechanism of nitrone bioactivity remains unclear. In this review, we present a
variety of nitrone chemistry and biological activity that could be implicated
for the nitrone's pharmacological activity. The chemistries of spin trapping and
spin adduct reveal insights on the possible roles of nitrones for altering
cellular redox status through radical scavenging or nitric oxide donation, and
their biological effects are presented. An interdisciplinary approach towards
the development of novel synthetic antioxidants with improved pharmacological
properties encompassing theoretical, synthetic, biochemical and in vitro/in vivo
studies is covered.
DOI: 10.4155/fmc.12.74
PMCID: PMC5248478
PMID: 22709256 [Indexed for MEDLINE]
Conflict of interest statement: Financial & competing interests disclosure The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this
manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/20132991 | 1. Psychiatry Res. 2010 Apr 30;176(2-3):174-8. doi:
10.1016/j.psychres.2008.11.012. Epub 2010 Feb 4.
Is there a CSF biomarker profile related to depression in elderly women?
Gudmundsson P(1), Skoog I, Waern M, Blennow K, Zetterberg H, Rosengren L,
Gustafson D.
Author information:
(1)Institute of Neuroscience and Physiology, Section for Psychiatry and
Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Sweden.
[email protected]
In light of our previous observation of higher levels of cerebrospinal fluid
(CSF) amyloid beta-42 (Abeta42) and CSF/serum albumin ratio in major depressive
disorder (MDD), we analyzed two additional CSF biomarkers reflecting
neurodegeneration-neurofilament protein light (NFL) and glial fibrillary acidic
protein (GFAp)-in relationship to prevalent geriatric depression.
Neuropsychiatric, physical, and lumbar puncture examinations, with
DSM-III-R-based depression diagnoses and measurement of CSF levels of NFL and
GFAp, were evaluated among a population-based sample of 78 elderly women (mean
age, 73.9+/-3.2 years) without dementia for at least 10 years after CSF
collection. Eleven (13.1%) women had MDD, and higher levels of NFL compared with
women without depression. A multivariate model including age, NFL, Abeta42 and
the CSF/serum albumin ratio showed that each biomarker was independently and
positively associated with MDD, and that this biomarker profile explained more
variation in the model compared with single or combined biomarkers. A CSF
profile with higher levels of NFL, Abeta42, and CSF/serum albumin ratio may
indicate neuropathological and vascular events in depression etiology. This
contrasts with the well-characterized pattern of low Abeta42, higher CSF/serum
albumin ratio, and higher NFL in Alzheimer's disease.
Copyright (c) 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.psychres.2008.11.012
PMID: 20132991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16467546 | 1. N Engl J Med. 2006 Feb 9;354(6):588-600. doi: 10.1056/NEJMoa052980.
NXY-059 for acute ischemic stroke.
Lees KR(1), Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, Grotta J, Lyden
P, Shuaib A, Hårdemark HG, Wasiewski WW; Stroke-Acute Ischemic NXY Treatment
(SAINT I) Trial Investigators.
Collaborators: Lees KR, Zivin JA, Ashwood T, Davalos A, Davis S, Diener E,
Grotta J, Lyden P, Kakarieka A, Sheth S, Shuaib A, Wasiewski W, Pocock S, Adams
H, Bath P, Oakes D, Wahlgren NG, Söderberg K, Hårdemark HG, Alderfer V, Grönblad
A, Emeribe U, Staples C, Bladin C, Levi C, Davis S, Dunbabin D, Schultz D,
Crimmins D, Donnan G, Gerraty R, Thijs V, Willems C, De Deyn P, Vanhooren G,
Desfontaines P, Caekebeke J, Etienne U, Stamenova P, Platikanov V, Baldaranov D,
Minchev D, Tunev A, Nocheva T, Bar M, Vaclavik D, Lachmann H, Ehler E, Bauer J,
Skoda O, Waberzinek G, Keller O, Urbanek K, Rektor I, Kalvach P, Meden P,
Andersen G, Kaste M, Koivisto K, Rissanen A, Numminen H, Muuronen A, Amarenco P,
Bonafe A, Ziegler F, Boulliat J, Moulin T, Clavelou P, Sablot D, Rollet E,
Lavage P, Lucas C, Guillon B, Schneider D, Vogel P, Glahn J, Hamann GF, Weiller
C, Hetzel A, Diener C, Hennerici M, Eicke M, Deuschl G, Lachenmayer L, Sander D,
Witte OW, Sliwka U, Widder B, Meves S, Ng PW, Ka Sing Wong L, Cheung R, Nagy Z,
Béla C, Gyula K, Csányi A, Sándor H, Lászlo C, Micieli G, Agnelli G, Gandolfo C,
Carolei A, Guidetti D, Inzitari D, Merican JS, Bee Fung S, Kay--Sin T, Azman Ali
R, Anderson C, Barber A, Fink J, Gommans J, Keizer K, van Erven PM, Brouwers PJ,
Veering MM, Dippel D, Kwa VI, Franke CL, Kleyweg RP, Boon AE, Bjerke P,
Thomassen L, Indredavik J, Hermstad B, Salvesen R, Jörgensen E, Czlonkowska A,
Kuczynska A, Freyze W, Wlodek A, Wlodek A, Vasco Salgado A, Cunha L, Gonçalves
G, Correia M, Ng I, Hui Meng C, Chan B, Dvorák M, Brozman M, Kurca E, Garay R,
Bratislava, Vyletelka J, Nyéky M, Herényiová J, Thorne J, Maritz F, Green J,
Badenhorst H, Gardiner J, Lurie D, van Graan E, Lee BC, Kim JS, Lee KH, Roh JK,
Lee YS, Serena Leal J, Alvarez Sabin J, Gil Peralta A, Rubio F, Roquer J,
Fernández-Bolanos R, Dávalos A, Castillo J, Guiu JM, Diez Tejedor E, Vivancos J,
Lluis Martí i Vilalta J, Mostacero E, Chamorro A, Gil Nunez A, Lago A, Egido JA,
Callander M, Petersson J, Terent A, Käll TB, Kostulas V, Leijd B, Karlsson JE,
Karlsson S, Lees KR, Ford GA, Muir K, Barer D, Sharma A, Jenkinson D, Gray C,
MacWalter R, Robinson T.
Author information:
(1)Acute Stroke Unit and Cerebrovascular Clinic, University Department of
Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow,
United Kingdom. [email protected]
Comment in
N Engl J Med. 2006 Feb 9;354(6):553-5. doi: 10.1056/NEJMp058312.
N Engl J Med. 2006 May 11;354(19):2075-6; author reply 2075-6. doi:
10.1056/NEJMc060685.
N Engl J Med. 2006 May 11;354(19):2075-6; author reply 2075-6.
BACKGROUND: NXY-059 is a free-radical-trapping agent that is neuroprotective in
animal models of stroke. We tested whether it would reduce disability in humans
after acute ischemic stroke.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial
involving 1722 patients with acute ischemic stroke who were randomly assigned to
receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours
after the onset of the stroke. The primary outcome was disability at 90 days, as
measured according to scores on the modified Rankin scale for disability (range,
0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound,
requiring constant care).
RESULTS: Among the 1699 subjects included in the efficacy analysis, NXY-059
significantly improved the overall distribution of scores on the modified Rankin
scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test).
The common odds ratio for improvement across all categories of the scale was
1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of
serious and nonserious adverse events were each similar in the two groups.
NXY-059 did not improve neurologic functioning as measured according to the
National Institutes of Health Stroke Scale (NIHSS): the difference between the
two groups in the change from baseline scores was 0.1 point (95 percent
confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed
according to the Barthel index (P=0.14). In a post hoc analysis of patients who
also received alteplase, NXY-059 was associated with a lower incidence of any
hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage
(P=0.036).
CONCLUSIONS: The administration of NXY-059 within six hours after the onset of
acute ischemic stroke significantly improved the primary outcome (reduced
disability at 90 days), but it did not significantly improve other outcome
measures, including neurologic functioning as measured by the NIHSS score.
Additional research is needed to confirm whether NXY-059 is beneficial in
ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).
Copyright 2006 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa052980
PMID: 16467546 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19074479 | 1. Stroke. 2009 Feb;40(2):577-81. doi: 10.1161/STROKEAHA.108.524330. Epub 2008
Dec 12.
Methodological quality of animal studies of neuroprotective agents currently in
phase II/III acute ischemic stroke trials.
Philip M(1), Benatar M, Fisher M, Savitz SI.
Author information:
(1)Department of Neurology, University of Texas Houston Medical School, Houston,
TX 77030, USA.
Comment in
Stroke. 2009 Jul;40(7):e497. doi: 10.1161/STROKEAHA.109.550335.
BACKGROUND AND PURPOSE: Numerous neuroprotective agents have proven effective in
animal stroke studies, but every drug has failed to achieve its primary outcome
when brought forward to clinical trials. We analyzed the quality and adequacy of
animal studies supporting the efficacy of NXY-059 and other neuroprotective
agents that are currently being investigated in phase II/III trials.
METHODS: We conducted a systematic search of all neuroprotective drugs in Phase
II or III trials and collected data from animal studies of focal cerebral
ischemia testing agents systemically administered within 24 hours of occlusion.
The methodological rigor of each individual study was evaluated using 5 criteria
derived from the STAIR guidelines. The adequacy of the preclinical "package" for
each drug was then evaluated by combining the results of all studies for each
drug to determine which of a further 5 STAIR criteria were met before moving
forward from animal to human studies.
RESULTS: Our search yielded 13 agents of which 10 had published data in
peer-reviewed journals. There is substantial within-drug variability in the
quality of preclinical studies as well as substantial variation in the
completeness of the collective preclinical literature for different drugs. There
has been little or no improvement in the quality of animal studies since
NXY-059, and current agents have not been subjected to a more complete
preclinical evaluation.
CONCLUSIONS: There is significant heterogeneity in the quality of animal testing
for neuroprotective agents in stroke. Drugs in the post-SAINT era have not been
subjected to more thorough preclinical evaluation.
DOI: 10.1161/STROKEAHA.108.524330
PMID: 19074479 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22075627 | 1. Clin Exp Metastasis. 2012 Feb;29(2):101-10. doi: 10.1007/s10585-011-9433-5.
Epub 2011 Nov 11.
CXCR4/CXCL12 expression profile is associated with tumor microenvironment and
clinical outcome of liver metastases of colorectal cancer.
Sakai N(1), Yoshidome H, Shida T, Kimura F, Shimizu H, Ohtsuka M, Takeuchi D,
Sakakibara M, Miyazaki M.
Author information:
(1)Department of General Surgery, Chiba University Graduate School of Medicine,
Inohana, Chuo-ku, Chiba, Japan.
Interaction between CXCR4 and CXCL12 plays a role in tumor progression. The
present study examined CXCR4, CXCL12 and CD133 expression in liver metastases of
colorectal cancer (CLM) and determined whether the expression profiles affect
the tumor microenvironment and thus progression, and whether they could serve as
a prognostic marker for survival. Liver metastases of colorectal cancer
collected from 92 patients were evaluated by CXCR4, CXCL12 and CD133
immunohistochemistry and clinicopathological data were analyzed. The expression
profile of CXCR4 was determined in the colorectal cancer cell line, SW48. The
expression of cytoplasmic CXCR4 was higher in 36 (39%) patients than that
indicated by CXCR4 staining intensity of hepatocytes. High levels of nuclear
CXCR4 expression in 23 (25%) patients significantly correlated with CXCL12
expression in hepatocytes. Nuclear CXCR4 expression was increased in the cancer
cells after exposure to CXCL12. Univariate and multivariate analyses
demonstrated that the high levels of nuclear CXCR4 and CXCL12 expression in
hepatocytes were significantly better prognostic factors for overall and hepatic
disease-free survival in patients with CLM. The expression of CXCR4 and CXCL12
in CLM may have an interactive effect that could alter the tumor
microenvironment. CXCR4 expression in metastatic liver tumors together with the
upregulation of CXCL12 in hepatocytes may help to predict the clinical outcomes
of patients with CLM after hepatectomy.
DOI: 10.1007/s10585-011-9433-5
PMID: 22075627 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17068304 | 1. Stroke. 2006 Dec;37(12):2970-8. doi: 10.1161/01.STR.0000249410.91473.44. Epub
2006 Oct 26.
Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke
in the SAINT I trial.
Lees KR(1), Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Ashwood
T, Hardemark HG, Wasiewski W, Emeribe U, Zivin JA; SAINT I Investigators.
Author information:
(1)Acute Stroke Unit & Cerebrovascular Clinic, University Department of Medicine
& Therapeutics, Gardiner Institute, Western Infirmary, 44 Church St, Glasgow,
Scotland G11 6NT. [email protected]
BACKGROUND AND PURPOSE: NXY-059 is a free radical-trapping neuroprotectant
demonstrated to reduce disability from ischemic stroke. We conducted analyses on
additional end points and sensitivity analyses to confirm our findings.
METHODS: We randomized 1722 patients with acute ischemic stroke to a 72-hour
infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The
primary outcome was disability at 90 days, as measured by the modified Rankin
Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5
(bed-bound, requiring constant care). Additional and exploratory analyses
included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments
of activities of daily living by Barthel index; and National Institutes of
Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.
RESULTS: NXY-059 significantly improved the distribution of the mRS disability
score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test
P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01
to 1.42). The benefit was not attributable to any specific baseline
characteristic, stratification variable or subgroup interaction. Neurological
scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89;
P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI,
1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).
CONCLUSIONS: NXY-059 within 6 hours of acute ischemic stroke significantly
reduced disability. Benefit on neurological scores and activities of daily
living was detectable early but not significant at 90 days; however, our trial
was underpowered to measure effects on the neurological examination. The benefit
on disability is not confounded by interactions and is supported by other
outcome measures.
DOI: 10.1161/01.STR.0000249410.91473.44
PMID: 17068304 [Indexed for MEDLINE] |