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Kan Chen Wanlu Cao Juan Li Dave Sprengers Pratika Y Hernanda Xiangdong Kong Luc JW van der Laan Kwan Man Jaap Kwekkeboom Herold J Metselaar Maikel P Peppelenbosch Qiuwei Pan 《Molecular medicine (Cambridge, Mass.)》2015,21(1):792-802
As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA. 相似文献
14.
Han-Seop Bea Sang-Hyeup Lee Hyungdon Yun 《Biotechnology and Bioprocess Engineering》2011,16(2):291-296
In this study, (R)-3-fluoroalanine was asymmetrically synthesized from 3-fluoropyruvate (F-pyruvate) and (S)-α-methylbenzylamine (MBA) using recombinant ω-transaminase (TA) from Vibrio fluvialis JS17. The reaction was severely inhibited by acetophenone (deaminated product of α-MBA). In the presence of 5 mM acetophenone,
the reactivity of the enzyme towards F-pyruvate decreased by 78%. To overcome the product inhibition by acetophenone, a biphasic
reaction was successfully used. The conversion of F-pyruvate into (R)-3-fluoroalanine (enatiomeric exess (e.e.) > 99%) was about 95% in the biphasic system (75 mM F-pyruvate, 100 mM (S)-α-MBA, and 3.0 U/mL), whereas 31% was obtained without product extraction. The use of racemic α-MBA as an amino donor instead
of (S)-α-MBA can reduce the reaction cost and also produce chiral amines through kinetic resolution. When the kinetic resolution
of racemic α-MBA (40 mM) was carried out with F-pyruvate (30 mM) and ω-TA (3.0 U/mL) in 100 mM phosphate buffer (pH 7.0),
the e.e. of (R)-α-MBA reached 98.4% with 52.2% conversion for 10 h and 21 mM (R)-3-fluoroalanine was produced with 70% conversion and an e.e. > 99%. 相似文献
15.
Vegliante MC Royo C Palomero J Salaverria I Balint B Martín-Guerrero I Agirre X Lujambio A Richter J Xargay-Torrent S Bea S Hernandez L Enjuanes A Calasanz MJ Rosenwald A Ott G Roman-Gomez J Prosper F Esteller M Jares P Siebert R Campo E Martín-Subero JI Amador V 《PloS one》2011,6(6):e21382
Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications. 相似文献
16.
Pauwels B Korst AE Andriessen V Baay MF Pattyn GG Lambrechts HA Pooter CM Lardon F Vermorken JB 《Radiation research》2005,164(5):642-650
Gemcitabine has excellent radiosensitizing properties, as shown in both preclinical and clinical studies. Radiosensitization correlated with the early S-phase block of gemcitabine. In the present study, we investigated the role of TP53 in the radiosensitizing effect of gemcitabine. Isogenic A549 cells differing in TP53 status were treated with gemcitabine during the 24 h prior to irradiation. Cell survival was determined 7 days after irradiation by the sulforhodamine B test. In addition, cell cycle perturbation was determined by flow cytometry and TP53 expression by Western blot analysis. Gemcitabine caused a concentration-dependent radiosensitizing effect in all cell lines. Transformed A549 cells were less sensitive to the cytotoxic effect of gemcitabine. The cell cycle arrest early in the S phase was dependent on the drug dose but was comparable in the different cell lines and was not related to functional TP53. Using isogenic cell lines, we have shown that neither TP53 status nor the transfection procedure influenced the radiosensitizing effect of gemcitabine. Since both the radiosensitizing effect at equitoxic concentrations and the cell cycle effect of gemcitabine were independent of TP53 expression, it is likely that TP53 protein does not play a crucial role in the radiosensitizing mechanism of gemcitabine. 相似文献
17.
Fife MS Gutierrez A Ogilvie EM Stock CJ Samuel JM Thomson W Mack LF Lewis CM Woo P 《Arthritis research & therapy》2006,8(5):R148-5
Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease
subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This
study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with
sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP)
in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype
analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031)
and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for
association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082
genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T
haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important
role for these cytokines in sJIA pathogenesis. 相似文献
18.
Köck R Loth B Köksal M Schulte-Wülwer J Harlizius J Friedrich AW 《Applied and environmental microbiology》2012,78(11):4046-4047
Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is frequently transmitted from pigs to farmers. This study analyzed whether an absence from direct contact with pigs during holidays had an impact on nasal MRSA colonization rates of pig farmers. Overall, 59% of the farmers did not clear MRSA colonization during their leave. 相似文献
19.
Bea Vuylsteke Gis��le Semd�� Lazare Sika Tania Crucitti Virginie Etti��gne Traor�� Anne Buv�� Marie Laga 《PloS one》2012,7(3)
Objective
To assess condom use and prevalence of STIs and HIV among female sex workers (FSWs), as part of a comprehensive monitoring and evaluation plan of a nationwide sex worker prevention project in Côte d''Ivoire.Design and Methods
Cross sectional surveys were conducted among FSWs attending five project clinics in Abidjan and San Pedro (2007), and in Yamoussoukro and Gagnoa (2009). A standardized questionnaire was administered in a face-to-face interview, which included questions on socio-demographic characteristics, sexual behaviour and condom use. After the interview, the participants were asked to provide samples for STI and HIV testing.Results
A total of 1110 FSWs participated in the surveys. There were large differences in socio-demographic and behavioural characteristics between FSW coming for the first time as compared to FSW coming on a routine visit. The prevalence of N. gonorrhoeae or C.trachomatis was 9.1%, 11.8% among first vs. 6.9% routine attendees (p = 0.004). The overall HIV prevalence was 26.6%, it was lower among first time attendees (17.5% as compared to 33.9% for routine attendees, p<0.001). The HIV prevalence among first attendees was also lower than the proportion of HIV positive tests from routine testing and counselling services in the same clinics.Conclusions
The results show a relatively high STI and HIV prevalence among FSWs in different cities in Côte d''Ivoire. In the light of these results, prevention efforts should continue to focus on FSWs in the country. 相似文献20.
ágnes Lendvai Frank Johannes Christina Grimm Jasper J.H. Eijsink René Wardenaar Haukeline H. Volders Harry G. Klip Harry Hollema Ritsert C. Jansen Ed Schuuring G. Bea A. Wisman Ate G.J. van der Zee 《Epigenetics》2012,7(11):1268-1278
Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2–94.7% high-grade CIN and in 59.3–100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection. 相似文献