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Background-Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study. Methods and Results-One hundred seventy-six consecutive patientsdoi:10.1161/01.cir.97.2.147 pmid:9445166 fatcat:ube4cjpfcndzjpe6hpz3ekbrmu
more »... successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels ( ϮSEM) were 40.8Ϯ3.5 and 20.7Ϯ1.0 U/L, respectively (PϽ.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (rϭ.352 and Ϫ.387, respectively PϽ.001). Twenty-one of 62 patients (33.9%) with D/D genotype, 13 of 80 (16.3%) with I/D genotype, and 1 of 34 (2.9%) with I/I genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele D. Conclusions-In a selected cohort of patients, both the D/D genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted. (Circulation. 1998;97:147-154.)
Leukocyte telomere length (LTL) provides a potential marker of biological age, closely related to the endothelial dysfunction and consequently to the atherosclerotic process. To investigate the relationship between the LTL and the risk of premature acute myocardial infarction and to evaluate the predictive value of LTL on the onset of major cardiovascular events, 199 patients from 18 to 48 years old with first diagnosis of acute myocardial infarction were enrolled and were matched with 190doi:10.1371/journal.pone.0049206 pmid:23145125 pmcid:PMC3492293 fatcat:x7lc7llvwrc55hdkm53yjux2qa
more »... ols for sex and age (61 year). Clinical data and coronary artery disease were evaluated at enrollment and at follow up. LTL was measured at enrollment using a quantitative PCR-based method. No significant differences were observed in LTL between cases and controls (p = 0.20) and with the presence of coronary artery disease in patients (p = 0.47). Hypercholesterolemic cases presented LTL significantly longer than cases without hypercholesterolemia (t/s: 0.8260.16 p = 0.79 and t/s norm: 0.7960.19 p = 0.01), as confirmed in multivariate regression analysis (p = 0.005, b = 0.09). Furthermore, multivariate regression analysis showed LTL significantly shorter in hypertensive cases than in normotensive cases (p = 0.04, b = 20.07). One hundred seventy-one cases (86%) ended the average follow up of 965 years, 92 (54%) presented a major cardiovascular event. At multivariate regression analysis the LTL detected at enrollment did not represent a predictive factor of major cardiovascular events nor it significantly impacted with cumulative events. Based on present cohort of young Italian patients, the LTL did not represent a marker of acute myocardial infarction nor had a predictive role at medium term follow up.
Zhuo et al 1 reported interesting observations in vivo about the effects of angiotensin-converting enzyme (ACE) inhibition with perindopril on plasma ACE levels and cellular expression of ACE, AT 1 receptors, and nitric oxide synthase (NOS) isoforms in human blood vessels. Oral ACE inhibition at conventional doses (perindopril 4 mg/d) decreased plasma ACE activity by 70% and vascular ACE immunoactivity to 65% of control subjects detected by immunocytochemistry, and increased endothelial NOSdoi:10.1161/01.hyp.0000035252.27580.77 pmid:12364366 fatcat:wwlgygz47vgntafvuawvz44x6u
more »... S) and inducible NOS (iNOS) expression in the vascular wall. However, the authors also observed a dramatic 80% increment of the AT 1 receptor binding in vascular smooth muscle cells, which might increase the potential of these receptors to counterbalance the beneficial effects of suppressed angiotensin II formation if AT 1 receptors were activated by alternative sources of angiotensin II. Whether the overexpression of AT 1 receptors may somehow limit, or even reverse, the beneficial effects of ACE inhibitors in specific clinical situations of vascular disease has stimulated the following comments. So far, mostly beneficial vascular effects have been reported in patients treated with ACE inhibitors. 2,3 However, 2 recent publications have shown that oral administration of ACE inhibitors following stented angioplasty actually augmented the incidence of restenosis instead of reducing it. 4,5 Conversely, the administration of AT 1 antagonist valsartan in the VAL-PREST Trial reduced the occurrence of stent restenosis in a small but placebo-controlled randomized trial. 6 Although these studies were not aimed at evaluating the clinical outcome, the angiographic findings are consistent with an opposite-to-the-expected effect of ACE inhibitors and a possible favorable outcome with AT 1 antagonists. In-stent restenosis is a proliferative response of the vessel wall to the injury caused by coronary stenting, and this phenomenon correlates in humans with plasma ACE concentration. 7,8 Furthermore, tissue ACE is upregulated locally during the vascular healing process. 9 ACE inhibition was thought to potentially contribute to the prevention of its occurrence, but emerging evidence does not support this hypothesis. A large angiographic analysis addressing this issue is being performed by our group. 10 Although retrospective in nature, the preliminary analysis of nearly 1000 consecutive patients yielded a much higher restenosis rate in 282 ACE-inhibited patients (36.6%) compared with 615 nontreated patients (22.9%) (ORϭ1.94, 95% CI: 1.45-2.59). Such a difference persisted after normalization for covariates. By multivariate analysis, ACE inhibition emerged as an independent predictor of stent restenosis (ORϭ1.84, 95%CI: 1.35-2.52, Pϭ0.001). 10 Zhuo et al 1 provide a valuable piece of information that supports these observations and allows us to speculate that the interactions between plasma and tissue ACE levels and the intracellular signaling of angiotensin II in patients treated with ACE inhibitors may be involved in the mechanisms that lead to exuberant neointimal growth through the over-expression of AT 1 membrane receptors. This might happen as a consequence of the chronic enzyme depletion that induces AT 1receptor over-expression and/or enhanced intracellular signaling of angiotensin II formed by the noninhibited fraction of plasma ACE, or by alternative metabolic pathways such as ACE-independent, chymase-mediated angiotensin II. The integration of the evidence briefly summarized in this letter supports the hypothesis formulated to explain the augmented incidence of in-stent restenosis in ACE-inhibited patients. 1. Zhuo JL, Mendelsohn FAO, Ohishi M. Perindopril alters vascular angiotensin-converting enzyme, AT 1 receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension. 2002;39(pt 2):634 -638. 2. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, Pitt B. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection: current perspective. Circulation. 1994;90:2056 -2069. 3. Yusuf S, Sleiht P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. 4. Meurice T, Bauters C, Hermant X, Codron V, VanBelle E, Mc Fadden EP, Lablanche JM, Bertrand ME, Amouyel P. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomized, double-blind, placebo-controlled trial.
Polymorphisms in regulatory DNA regions are believed to play an important role in determining phenotype, including disease, and in providing raw material for evolution. We devised a new pipeline for the systematic identification of functional variation in human regulatory sequences. The algorithm is based on the identification of SNPs leading to significant changes in both the affinity of a regulatory region for transcription factors and the expression in vivo of the regulated gene. We testeddoi:10.1002/humu.22299 pmid:23420607 fatcat:ee4ffblrcfh4xcrbfcewcphl6e
more »... e algorithm by identifying SNPs leading to altered regulation by STAT3 in human promoters and introns, and experimentally validated the top-scoring ones, showing that most of the SNPs identified by the algorithm indeed correspond to differential binding of STAT3 and differential induction of the target gene upon stimulation with IL6. Using the same computational approach we compiled a database of thousands of predicted functional regulatory SNPs for hundreds of human transcription factors which we provide as a public resource. We discuss possible applications to the interpretation of non-coding SNPs associated to human diseases. The method we propose and the database of predicted functional cis-regulatory polymorphisms will be useful in future studies of regulatory variation and in particular to interpret the results of past and future genome-wide association studies.
We present a meta-analysis to test the hypothesis that the presence of a high level of bulky DNA adducts in tissues is associated with an increased risk of cancer in humans. Seven articles were selected that matched the selection criteria, for a total of 691 cancer patients and 632 control subjects. In five studies the cases had lung cancer, in one oral cancer, and in one bladder cancer. Six studies measured adducts in WBCs and one in normal lung tissue around tumor tissue. Six werepmid:12582026 fatcat:7hqnjx7iafahlbflrk6qjzjdbq
more »... investigations, and one was a case-control study on lung cancer nested within a cohort. Current smokers showed a statistically significant difference between cases and controls, with cases having 83% higher levels of adducts than controls (95% confidence interval, 0.44-1.22). Results were negative or contradictory in ex-smokers and nonsmokers. This observation was confirmed by sensitivity analyses. Publication bias does not seem to be a problem. Despite some methodological limitations, our meta-analysis shows that current smokers with high levels of adducts have an increased risk of lung and bladder cancers. This conclusion also suggests that similar (aromatic) compounds may be involved in the etiology of both types of cancer.
The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which thedoi:10.3390/ijms22189740 pmid:34575904 fatcat:qqz6gmibdbetpkv4q45pz7sube
more »... methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions.
2018-2022" to Department of Medical Sciences (Giuseppe Matullo), University of Torino. ... Acknowledgments: This work was supported by Compagnia di San Paolo-IIGM (to Giuseppe Matullo) and by Ministero dell'Istruzione, dell'Università e della Ricerca-MIUR project "Dipartimenti di Eccellenza ...doi:10.3390/ijms19030688 pmid:29495593 pmcid:PMC5877549 fatcat:eix5fr6hcrdzrnsaexbe53orfq
.; Matullo G.; Piazza A.; Ursino M.; Gasparini M. (2013). A proximity-based method to identify genomic regions correlated with a continuously varying environmental variable. ...doi:10.4137/ebo.s10211 pmid:23423242 pmcid:PMC3565544 fatcat:ctjkutql3zfypjxcfjzanwteyy
Exposure to cigarette smoking affects the epigenome and could increase the risk of developing diseases such as cancer and cardiovascular disorders. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to disease etiology. Previous studies are not completely concordant in the identification of differentially methylated regions in the DNA of smokers. We performed an epigenome-wide DNA methylation study in a group of monozygotic (MZ) twinsdoi:10.1371/journal.pone.0128265 pmid:26043106 pmcid:PMC4456379 fatcat:a5idvlbonjblrmoofvwoepnusu
more »... rdant for smoking habits to determine the effect of smoking on DNA methylation. As MZ twins are considered genetically identical, this model allowed us to identify smoking-related DNA methylation changes independent from genetic components. We investigated the whole blood genome-wide DNA methylation profiles in 20 MZ twin pairs discordant for smoking habits by using the Illumina Human-Methylation450 BeadChip. We identified 22 CpG sites that were differentially methylated between smoker and non-smoker MZ twins by intra-pair analysis. We confirmed eight loci already described by other groups, located in AHRR, F2RL3, MYOG1 genes, at 2q37.1 and 6p21.33 regions, and also identified several new loci. Moreover, pathway analysis showed an enrichment of genes involved in GTPase regulatory activity. Our study confirmed the evidence of smoking-related DNA methylation changes, emphasizing that well-designed MZ twin models can aid the discovery of novel DNA methylation signals, even in a limited sample population.
(9) in a companion GWAS study on MPM observed other associated SNPs but failed to replicate results from Matullo et al. (8) . ... Study sample Interaction analysis was conducted using genotypic frequencies and sample information from the GWAS by Matullo et al. (8) . ...doi:10.1093/carcin/bgv097 pmid:26139392 fatcat:c2hk6yopcrhlxc5rv62y7nqwwq
The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods -fixation index, inflation factor, principal component analysis and ancestry estimationdoi:10.1371/journal.pone.0091237 pmid:24651212 pmcid:PMC3961211 fatcat:xqxjhcms4bbyhmau35xg7esroi
more »... e were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs.0.5 Mb (F RoH%0.5 ) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces.
VOLUME 22 - NUMBER 19 - OCTOBER 1 2004 JOURNAL OF CLINICAL ONCOLOGY IGINAL REPORT Association Between Aryl Hydrocarbon Receptor Genotype and Survival in Soft Tissue Sarcoma Marianne Berwick, Giuseppe Matullo ...doi:10.1200/jco.2004.10.059 pmid:15459223 fatcat:op4uwcrlbrfw7plr77t44ld2hu
Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. It is routinely cured by a 5-fl uorouracil (5-FU)-based chemotherapy which improves outcomes in patients. We investigated the effect of single nucleotide polymorphisms (SNPs) in two microRNA (miRNA)-encoding genes that have been previously reported as important in prognosis in patients with stage III CRC and treated with 5-FU-based chemotherapy. Two SNPs (rs4919510 in miR-608 and rs213210 in miR-219-1) weredoi:10.1093/carcin/bgu224 pmid:25368035 fatcat:luvkt2x5bfh7tnlo2ykhff3gfm
more »... enotyped in 1083 CRC patients recruited in the Czech Republic to evaluate their effect on clinical outcomes. Carriers of the variant T allele in rs213210 and receiving 5-FU chemotherapy were associated with a significantly worse survival [hazard ratio (HR) = 2.18; 95% confidence interval (CI): 1.20-3.98; adjusted P = 0.01] and an increased risk of relapse (HR = 1.94; 95% CI: 1.16-3.25; adjusted P = 0.01). After further stratification for tumor grading, stage III patients carrying the G allele of rs4919510 and undergoing adjuvant chemotherapy were at decreased risk of relapse (HR = 0.44; 95% CI: 0.20-0.94; adjusted P = 0.03). The present study confirms that variations in miRNA-encoding genes may be an important factor for modulating CRC prognosis and predicting therapy response.
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