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21.
Rob Noorlag Pauline MW van Kempen Cathy B Moelans Rick de Jong Laura ER Blok Ronald Koole Wilko Grolman Paul J van Diest Robert JJ van Es Stefan M Willems 《Epigenetics》2014,9(9):1220-1227
Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis and a potential target for personalized cancer treatment. In head and neck cancer, little is known about the role of promoter hypermethylation in survival. Using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) we investigated the role of promoter hypermethylation of 24 well-described genes (some of which are classic TSGs), which are frequently methylated in different cancer types, in 166 HPV-negative early oral squamous cell carcinomas (OSCC), and 51 HPV-negative early oropharyngeal squamous cell carcinomas (OPSCC) in relation to clinicopathological features and survival. Early OSCC showed frequent promoter hypermethylation in RARB (31% of cases), CHFR (20%), CDH13 (13%), DAPK1 (12%), and APC (10%). More hypermethylation (≥ 2 genes) independently correlated with improved disease specific survival (hazard ratio 0.17, P = 0.014) in early OSCC and could therefore be used as prognostic biomarker. Early OPSCCs showed more hypermethylation of CDH13 (58%), TP73 (14%), and total hypermethylated genes. Hypermethylation of two or more genes has a significantly different effect on survival in OPSCC compared with OSCC, with a trend toward worse instead of better survival. This could have a biological explanation, which deserves further investigation and could possibly lead to more stratified treatment in the future. 相似文献
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23.
The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation,invasion, and adhesion 下载免费PDF全文
Wright JH Wang X Manning G LaMere BJ Le P Zhu S Khatry D Flanagan PM Buckley SD Whyte DB Howlett AR Bischoff JR Lipson KE Jallal B 《Molecular and cellular biology》2003,23(6):2068-2082
HGK (hepatocyte progenitor kinase-like/germinal center kinase-like kinase) is a member of the human STE20/mitogen-activated protein kinase kinase kinase kinase family of serine/threonine kinases and is the ortholog of mouse NIK (Nck-interacting kinase). We have cloned a novel splice variant of HGK from a human tumor line and have further identified a complex family of HGK splice variants. We showed HGK to be highly expressed in most tumor cell lines relative to normal tissue. An active role for this kinase in transformation was suggested by an inhibition of H-Ras(V12)-induced focus formation by expression of inactive, dominant-negative mutants of HGK in both fibroblast and epithelial cell lines. Expression of an inactive mutant of HGK also inhibited the anchorage-independent growth of cells yet had no effect on proliferation in monolayer culture. Expression of HGK mutants modulated integrin receptor expression and had a striking effect on hepatocyte growth factor-stimulated epithelial cell invasion. Together, these results suggest an important role for HGK in cell transformation and invasiveness. 相似文献
24.
Biased mutations and microsatellite variation 总被引:10,自引:6,他引:4
Mutation bias is one of the forces that may constrain the variation at
microsatellite loci. Here, we study the dynamics of population statistics
and the genetic distance between two populations under multiple stepwise
mutations with linear bias and random drift. Expressions are derived for
these statistics as functions of time, as well as at mutation-drift
equilibrium. Applying these expressions to published data on humans and
chimpanzees, the regression coefficient of mutation bias on allele size was
estimated to be at least between - 0.0064 and -0.013. The assumption of
mutational bias produces larger estimates of divergence times than are
obtained in its absence; in particular, the time of split between African
and non-African human populations is estimated to be between 183,000 and
222,000 years, assuming one-step mutations and no selection. With multistep
mutations, the divergence time is estimated to be lower.
相似文献
25.
Sarah V Holdridge Stacey A Armstrong Anna MW Taylor Catherine M Cahill 《Molecular pain》2007,3(1):1-8
The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca2+. The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in culture mediate mechanosensation in the intact animal. These data give further insight into the mechanosensitive ion channels expressed by somatosensory neurons and suggest FM dyes are an interesting tool for studying them. 相似文献
26.
Manon JM van Oosten Radboud JEM Dolhain Jan W Koper Elisabeth FC van Rossum Marieke Emonts Khik H Han Jacques MGW Wouters Johanne MW Hazes Steven WJ Lamberts Richard A Feelders 《Arthritis research & therapy》2010,12(4):R159
Introduction
The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity. 相似文献27.
Jessica AB van Nies Celina Alves Audrey LS Radix-Bloemen Cécile Gaujoux-Viala Tom WJ Huizinga Johanna MW Hazes Elisabeth Brouwer Bruno Fautrel Annette HM van der Helm-van Mil 《Arthritis research & therapy》2015,17(1)
IntroductionMorning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA).MethodsIn arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions.ResultsIn arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission.ConclusionsMorning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0616-3) contains supplementary material, which is available to authorized users. 相似文献28.
Gennady V. Pogorelko Parijat S. Juvale William B. Rutter Marion Hütten Thomas R. Maier Tarek Hewezi Judith Paulus Renier AL van der Hoorn Florian MW Grundler Shahid Siddique Vincenzo Lionetti Olga A. Zabotina Thomas J. Baum 《The Plant journal : for cell and molecular biology》2019,98(6):1000-1014
Plants mount defense responses during pathogen attacks, and robust host defense suppression by pathogen effector proteins is essential for infection success. 4E02 is an effector of the sugar beet cyst nematode Heterodera schachtii. Arabidopsis thaliana lines expressing the effector‐coding sequence showed altered expression levels of defense response genes, as well as higher susceptibility to both the biotroph H. schachtii and the necrotroph Botrytis cinerea, indicating a potential suppression of defenses by 4E02. Yeast two‐hybrid analyses showed that 4E02 targets A. thaliana vacuolar papain‐like cysteine protease (PLCP) ‘Responsive to Dehydration 21A’ (RD21A), which has been shown to function in the plant defense response. Activity‐based protein profiling analyses documented that the in planta presence of 4E02 does not impede enzymatic activity of RD21A. Instead, 4E02 mediates a re‐localization of this protease from the vacuole to the nucleus and cytoplasm, which is likely to prevent the protease from performing its defense function and at the same time, brings it in contact with novel substrates. Yeast two‐hybrid analyses showed that RD21A interacts with multiple host proteins including enzymes involved in defense responses as well as carbohydrate metabolism. In support of a role in carbohydrate metabolism of RD21A after its effector‐mediated re‐localization, we observed cell wall compositional changes in 4E02 expressing A. thaliana lines. Collectively, our study shows that 4E02 removes RD21A from its defense‐inducing pathway and repurposes this enzyme by targeting the active protease to different cell compartments. 相似文献
29.
Evolutionary transfer of ORF-containing group I introns between different subcellular compartments (chloroplast and mitochondrion) 总被引:10,自引:2,他引:8
Turmel M; Cote V; Otis C; Mercier JP; Gray MW; Lonergan KM; Lemieux C 《Molecular biology and evolution》1995,12(4):533-545
We describe here a case of homologous introns containing homologous open
reading frames (ORFs) that are inserted at the same site in the large
subunit (LSU) rRNA gene of different organelles in distantly related
organisms. We show that the chloroplast LSU rRNA gene of the green alga
Chlamydomonas pallidostigmatica contains a group I intron (CpLSU.2)
encoding a site-specific endonuclease (I-CpaI). This intron is inserted at
the identical site (corresponding to position 1931-1932 of the Escherichia
coli 23S rRNA sequence) as a group I intron (AcLSU.m1) in the mitochondrial
LSU rRNA gene of the amoeboid protozoon Acanthamoeba castellanii. The
CpLSU.2 intron displays a remarkable degree of nucleotide similarity in
both primary sequence and secondary structure to the AcLSU.m1 intron;
moreover, the Acanthamoeba intron contains an ORF in the same location
within its secondary structure as the CpLSU.2 ORF and shares with it a
strikingly high level of amino acid similarity (65%; 42% identity). A
comprehensive survey of intron distribution at site 1931 of the chloroplast
LSU rRNA gene reveals a rather restricted occurrence within the
polyphyletic genus Chlamydomonas, with no evidence of this intron among a
number of non- Chlamydomonad green algae surveyed, nor in land plants. A
parallel survey of homologues of a previously described and similar
intron/ORF pair (C. reinhardtii chloroplast CrLSU/A. castellanii
mitochondrial AcLSU.m3) also shows a restricted occurrence of this intron
(site 2593) among chloroplasts, although the intron distribution is
somewhat broader than that observed at site 1931, with site-2593 introns
appearing in several green algal branches outside of the Chlamydomonas
lineage. The available data, while not definitive, are most consistent with
a relatively recent horizontal transfer of both site-1931 and site- 2593
introns (and their contained ORFs) between the chloroplast of a
Chlamydomonas-type organism and the mitochondrion of an Acanthamoeba- like
organism, probably in the direction chloroplast to mitochondrion. The data
also suggest that both introns could have been acquired in a single event.
相似文献
30.
Y chromosome variation of mice and men 总被引:7,自引:5,他引:2
DNA sequences from the nonrecombining portion of the Y chromosome were
compared with autosomal and X-linked sequences from mice and humans to test
the neutral prediction that ratios of polymorphism to divergence are the
same for different genes. Intraspecific variation within Mus domesticus was
compared with divergence between M. domesticus and Mus caroli for Sry, a
region 5' to Sry, and four X-linked genes, Hprt, Plp, Amg, and Glra2. None
of these comparisons revealed significantly reduced variation on the Y
chromosome. Intraspecific variation within humans was compared with
divergence between humans and chimpanzees for three Y-linked loci (Zfy, the
YAP region, and the Sry region), seven X- linked loci (Il2rg, Plp, Hprt,
Gk, Ids, Pdhal, and Dmd), and the beta- globin locus on chromosome 11. In
these comparisons, the observed level of variation on the human Y
chromosome was slightly lower than expected, but was significantly lower in
only one case (Sry region vs. Dmd). These results suggest that the levels
of variability on the Y chromosome in mice and humans are close to expected
values given the effective population size and mutation rates for these
loci. There is at most only a modest reduction in variability that may be
attributed to natural selection (either genetic hitchhiking or background
selection).
相似文献