CpG Island Methylator Phenotype Associated with Tumor Recurrence in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma
ABSTRACT CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.
We investigated the methylation status of ten TSGs and CIMP in 115 samples of HCC and 48 samples of corresponding nonneoplastic liver tissues using a methylation-specific polymerase chain reaction.
The methylation frequencies of the ten genes examined in HCC were 40.0% for p14 ( ARF ), 60.9% for p15 ( INK4b ), 70.4% for p16 ( INK4a ), 34.8% for p73, 70.4% for GSTP1, 64.3% for MGMT, 13.0% for hMLH1, 59.1% for RARbeta, 82.6% for SOCS-1, and 80.9% for OPCML. CIMP+ (with six or more methylated genes) was detected in 68 (59.1%) of 115 HCCs and none of 48 nonneoplastic liver tissues. On stratified univariate analysis, patients with tumor-node-metastasis (TNM) stage I HCC with CIMP+ had significantly shorter overall survival (OS) (P = 0.002) and recurrence-free survival (RFS) (P = 0.042) than those with CIMP-. Furthermore, multivariate analysis revealed CIMP+ as an independent prognostic factor for both OS [hazard ratio (HR), 12.266; P = 0.015] and RFS (HR, 2.275; P = 0.032) in TNM stage I patients.
CIMP+ may specifically define a subgroup of patients with unfavorable outcome in TNM stage I HCC. Examination of CIMP status may be useful for stratifying prognosis of patients with early-stage HCC and identifying patients who are at higher risk for recurrence.
Conference Paper: Influence of growth rate on MBE surface phase diagrams[Show abstract] [Hide abstract]
ABSTRACT: Static and dynamic surface phase diagrams for boundaries between the reconstructions (2×4)⇔(3×1) and (3×1)⇔(4×2) in (001) GaAs have been studied in detail. The surface phase diagrams, investigated for the purpose of practical application, show the influence of varying the growth rate. This for the first time has been interpreted as resulting from the presence of Ga droplets. This interpretation is consistent with a model indicating that surface Ga clusters play a key role in MBE growthSemiconducting and Insulating Materials Conference, 2000. SIMC-XI. International; 02/2000
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ABSTRACT: Introduction and aimsChronic inflammation plays a major role in lung deterioration in cystic fibrosis (CF) patients and anti-inflammatory strategies have beneficial effects. To study the changes seen after a oneyear course of low-dose dietary supplements with a mixture of fatty acids in adult patients with CF in chronic inflammation, pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), quality of life and anthropometric parameters.Patients and methodSeventeen adult subjects with CF received 324mg of eicosapentaenoic, 216mg of docosahexaenoic, 480mg of linoleic and 258mg of gammalinolenic acid daily. We assessed inflammation markers, spirometry parameters, number and severity of respiratory exacerbations, antibiotic consumption, quality of life (St George's QoL), anthropometric parameters and serum phospholipid fatty acid composition.ResultsAt the end of the treatment period TNF alpha levels fell significantly and its soluble receptors (60 and 80) rose significantly. Levels of IgG and IgM anti-oxidised LDL antibodies fell significantly. Spirometry improved significantly. Annual respiratory exacerbations and days of antibiotic treatment fell significantly. The improvement in QoL was not significant. Serum levels of docosahexaenoic, total omega-3 and linoleic acid rose significantly and more favourable profiles were seen in monoenoic acids, arachidonic acid and the arachidonic/docosahexaenoic ratio. The fat-free mass and hand grip dynamometry improved significantly.Conclusions Low-dose supplements of n-3 and gammalinolenic fatty acids over a long period (one year) appears to improve pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), inflammatory and anthropometric parameters in adults with CF.ResumenIntroducciónLa afectación pulmonar es la causa más importante de morbimortalidad en la fibrosis quística (FQ) y la inflamación-infección bronquial crónica condiciona el deterioro progresivo de la función pulmonar. Los tratamientos destinados a reducir la respuesta inflamatoria podrían ser beneficiosos.ObjetivosValorar el efecto de la suplementación oral durante un año en pacientes adultos con FQ, de una combinación de ácidos grasos sobre parámetros respiratorios, antropométricos, inflamatorios, de calidad de vida y sobre el perfil de AG de los fosfolípidos séricos (AGFS).Pacientes y métodoDiecisiete pacientes recibieron diariamente durante un año: 324 mg de ácido eicosapentaenoico, 216 mg de ácido docosahexaenoico, 480 mg de ácido linoleico y 258 mg de ácido gammalinolénico. Se valoraron marcadores inflamatorios, parámetros espirométricos, reagudizaciones respiratorias, consumo de antibióticos, calidad de vida (St. George), antropometría y los AGFS.ResultadosAl final del tratamiento se observó, de forma significativa, una disminución de reagudizaciones y del consumo de antibióticos con mejoría de los parámetros espirométricos, de la masa magra y la dinamometría. Concomitantemente, se observó una reducción significativa de los anticuerpos anti-LDL oxidada (inmunoglobulina [Ig] G e IgM) y de los niveles séricos del factor de necrosis tumoral α, así como un incremento de sus receptores solubles. Los niveles de AGFS mejoraron con un aumento significativo de DHA, AG-omega-3 y ácido linoleico, y un descenso de monoinsaturados y del cociente araquidónico/DHA.ConclusionesLa suplementación con una mezcla definida de AG durante un año parece mejorar los parámetros respiratorios (espirométricos, reagudizaciones y consumo de antibióticos), inflamatorios y antropométricos en pacientes adultos con FQ.Archivos de Bronconeumología 02/2010; 46(2):70-77. DOI:10.1016/S1579-2129(10)70018-5 · 2.17 Impact Factor
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ABSTRACT: Abnormal DNA methylation is well established for breast cancer and contributes to its progression by silencing tumor suppressor genes. DNA methylation profiling platforms might provide an alternative approach to expression microarrays for accurate breast tumor subtyping. We sought to determine whether the distinction of the inflammatory breast cancer (IBC) phenotype from the non-IBC phenotype by transcriptomics could be sustained by methylomics. We performed methylation profiling on a cohort of IBC (N = 19) and non-IBC (N = 43) samples using the Illumina Infinium Methylation Assay. These results were correlated with gene expression profiles. Methylation values allowed separation of breast tumor samples into high and low methylation groups. This separation was significantly related to DNMT3B mRNA levels. The high methylation group was enriched for breast tumor samples from patients with distant metastasis and poor prognosis, as predicted by the 70-gene prognostic signature. Furthermore, this tumor group tended to be enriched for IBC samples (54% vs. 24%) and samples with a high genomic grade index (67% vs. 38%). A set of 16 CpG loci (14 genes) correctly classified 97% of samples into the low or high methylation group. Differentially methylated genes appeared to be mainly related to focal adhesion, cytokine-cytokine receptor interactions, Wnt signaling pathway, chemokine signaling pathways and metabolic processes. Comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). A significant correlation between methylation values and gene expression was shown for 4,981 of 6,605 (75%) genes. A subset of clinical samples of breast cancer was characterized by high methylation levels, which coincided with increased DNMT3B expression. Furthermore, an association was observed with molecular signatures indicative of poor patient prognosis. The results of the current study also suggest that aberrant DNA methylation is not the main force driving the molecular biology of IBC.PLoS ONE 09/2010; 5(9):e12616. DOI:10.1371/journal.pone.0012616 · 3.53 Impact Factor