Search

Background: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and is associated with high recurrence and mortality, despite recent advancements in therapeutic strategies. MicroRNA (miR) deregulation is associated with CRC development and recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse postoperatively.Methods: In this study ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141, miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in their expression levels between early relapsed (recurrences within 12 months after surgery) and non-early relapsed CRC patients. The validation study, including 50 early relapsed and 54 non-early relapsed patients, confirmed miR expression alterations in cancer tissue samples.Results: Using a miR real-time quantitative polymerase chain reaction (RT-qPCR), we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased, whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC tissue samples from the early relapsed patients than in those from the non-early relapsed patients. Disease-free survival and overall survival were significantly worse in the high miR-7, miR-141, and miR-494 expression subgroups and the low miR-93 and miR-195 expression subgroups (all P < 0.05). A panel of 6 miRs (miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6 % and a specificity of 71.4 %. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4 % and a specificity of 88.9 %.Conclusions: This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and is associated with high recurrence and mortality, despite recent advancements in therapeutic strategies. MicroRNA (miR) deregulation is associated with CRC development and recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse postoperatively., Methods: In this study ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141, miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in their expression levels between early relapsed (recurrences within 12 months after surgery) and non-early relapsed CRC patients. The validation study, including 50 early relapsed and 54 non-early relapsed patients, confirmed miR expression alterations in cancer tissue samples., Results: Using a miR real-time quantitative polymerase chain reaction (RT-qPCR), we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased, whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC tissue samples from the early relapsed patients than in those from the non-early relapsed patients. Disease-free survival and overall survival were significantly worse in the high miR-7, miR-141, and miR-494 expression subgroups and the low miR-93 and miR-195 expression subgroups (all P < 0.05). A panel of 6 miRs (miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6 % and a specificity of 71.4 %. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4 % and a specificity of 88.9 %., Conclusions: This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients.

Background: The microRNAs let-7 g and miR-221 have been demonstrated to be related to the glucose metabolism. This study assessed the serum levels of these two microRNAs in subjects with and without metabolic syndrome (MetS)., Results: The serum microRNA levels were detected in 102 subjects aged 40 to 80 years who were recruited from the general population. The status of MetS was defined by the Adult Treatment Panel III (ATP III) criteria modified for Asians. Subjects with histories of cardiovascular diseases or who were receiving treatment with hypoglycemic or lipid-lowering agents were excluded. The levels of both circulating microRNAs (let-7 g and miR-221) were higher in subjects with MetS (p = 0.004 and p = 0.01, respectively). The sex-specific analysis showed that the difference was more prominent in women (for both miRNAs, p < 0.05 in women and p > 0.1 in men). In the female subjects, increased expression of both microRNAs was associated with an increased number of MetS risk components (p = 0.002 for let-7 g and p = 0.022 for miR-221). Moreover, the elevation of serum let-7 g was significantly associated with a low level of high-density lipoprotein cholesterol (p = 0.022) and high blood pressure (p = 0.023). In contrast, the miR-221 level was not associated with any individual MetS risk component., Conclusions: The circulating levels of let-7 g and miR-221 displayed a female-specific elevation in individuals with metabolic syndrome.

Background: Atherosclerosis shares common pathogenic features with myocardial infarction (MI) and ischemic stroke. BRCA-1 associated protein (BRAP), a newly identified risk gene for MI, aggravates the inflammatory response in atherosclerosis. The aim of this study was to test the association between the BRAP gene and stroke in a Taiwanese population., Methods: A total of 1,074 stroke patients and 1,936 controls were genotyped for the functional SNP rs11066001. In our previous studies, the rare allele of this SNP has been repeatedly shown to exert a recessive effect. Therefore, in the current study, we tested for the same recessive model. First, the genotype distributions between all the controls and all the stroke cases were compared. Then to reduce heterogeneity, we explored several population subsets by selecting young stroke subjects (using 45 years of age as the cutoff point), age- and sex-comparable controls, plaque-free controls, and stroke subtypes., Results: We did not find any significant association for the entire data set (OR = 0.94, p = 0.74) or for the subset analyses using age- and sex-comparable controls (p = 0.70) and plaque-free controls (p = 0.91). Analyses of the four stroke subtypes also failed to show any significant associations (p = 0.42 - 0.98). For both young and old subjects, the GG genotype of rs11066001 was similar in the stroke cases and unmatched controls (8.1% vs. 9.4% in young subjects and 8.0% vs. 7.8% in old subjects). Comparing stroke cases with plaque-free controls also failed to find any significant association., Conclusions: The BRAP polymorphism may not play an important role in ischemic stroke in the studied population.

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.

Background: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis., Methods: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect., Results: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27)., Conclusions: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.

Background: Matrix metalloproteinase (MMP) is involved in the upper airway remodeling process. We hypothesized that genetic variants of the MMP-9 gene are associated with cases of chronic rhinosinusitis with nasal polyposis., Methods: We conducted a case-control study where 203 cases of chronic rhinosinusitis with nasal polyposis and 730 controls were enrolled. Three tagging single nucleotide polymorphisms (SNPs) and one promoter functional SNP rs3918242 were selected. Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. Haplotype analysis was also performed. Permutation was used to adjust for multiple testing., Results: All four SNPs were in HWE. The T allele of promoter SNP rs3918242 was associated with chronic rhinosinusitis with nasal polyposis under the dominant (nominal p = 0.023, empirical p = 0.022, OR = 1.62) and additive models (nominal p= 0.012, empirical p = 0.011, OR = 1.60). The A allele of rs2274756 has a nominal p value of 0.034 under the dominant model and 0.020 under the additive model. Haplotype analysis including the four SNPs showed a global p value of 0.015 and the most significant haplotype had a p value of 0.0045. We did not see any SNP that was more significant in the recurrent cases., Conclusions: We concluded that MMP-9 gene polymorphisms may influence susceptibility to the development of chronic rhinosinusitis with nasal polyposis in Chinese population.

We performed linkage and linkage disequilibrium (LD) mapping analyses to compare the power between microsatellite and single nucleotide polymorphism (SNP) markers. Chromosome-wide analyses were performed for a quantitative electrophysiological phenotype, ttth1, on chromosome 7. Multipoint analysis of microsatellite markers using the variance component (VC) method showed the highest LOD score of 4.20 at 162 cM, near D7S509 (163.7 cM). Two-point analysis of SNPs using the VC method yielded the highest LOD score of 3.98 in the Illumina SNP data and 3.45 in the Affymetrix SNP data around 152-153 cM. In family-based single SNP and SNP haplotype LD analysis, we identified seven SNPs associated with ttth1. We searched for any potential candidate genes in the location of the seven SNPs. The SNPs rs1476640 and rs768055 are located in the FLJ40852 gene (a hypothetical protein), and SNP rs1859646 is located in the TAS2R5 gene (a taste receptor). The other four SNPs are not located in any known or annotated genes. We found the high density SNP scan to be superior to microsatellites because it is effective in downstream fine mapping due to a better defined linkage region. Our study proves the utility of high density SNP in genome-wide mapping studies.

Background: Family studies are often conducted in a cross-sectional manner without long-term follow-up data. The relative contribution of a gene to a specific trait could change over the lifetime. The Framingham Heart Study offers a unique opportunity to investigate potential gene x time interaction. We performed linkage analysis on the body mass index (BMI) measured in 1970, 1978, and 1986 for this project., Results: We analyzed the data in two different ways: three genome-wide linkage analyses on each exam, and one genome-wide linkage analysis on the mean of the three measurements. Variance-component linkage analyses were performed by the SOLAR program. Genome-wide scans show consistent evidence of linkage of quantitative trait loci (QTLs) on chromosomes 3, 6, 9, and 16 in three measurements with a maximum multipoint LOD score > 2.2. However, only chromosome 9 has a LOD score = 2.14 when the mean values were analyzed. More interestingly, we found potential gene x environment interactions: increasing LOD scores with age on chromosomes 3, 9, and 16 and decreasing LOD scores on chromosome 6 in the three exams., Conclusion: The results indicate two points: 1) it is possible that a gene (or genes) influencing BMI is (are) up- or down-regulated as people aged due to aging process or changes in lifestyle, environments, or genetic epistasis; 2) using mean values from longitudinal data may reduce the power to detect linkage and may have no power to detect gene x time, and/or gene x gene interactions.