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OBJECTIVE: To report our experience of fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS), with a focus on the postnatal evolution of the patients. METHODS: This was a retrospective study including all fetuses with critical AS which underwent FAV in a single center between January 2011 and June 2022. FAV was performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the antegrade aortic flow across the aortic valve. At birth, a biventricular circulation (BVC) strategy was decided assuming the left ventricular (LV) systolic and diastolic function would ensure the systemic circulation. RESULTS: Sixty-three FAV procedures were performed in 58 fetuses, at a median (range) gestational age of 26.2 (20.3-32.2) weeks. The procedure was technically successful in 50/58 (86.2%) fetuses. There were 11/58 (19.0%) cases of in-utero demise and 9/58 (15.5%) terminations of pregnancy. No patient was liveborn after an unsuccessful procedure. Thirty-eight (65.5%) infants were liveborn, at a median (range) gestational age of 38.1 (29.0-40.6) weeks, of whom 21 (55.3%) required prostaglandin treatment. Twenty-eight of the 38 (73.7%) liveborn children (48.3% of the study population) entered the BVC pathway at birth. Among them, 20 (71.4%) required an aortic valvuloplasty procedure at birth (11 (55.0%) percutaneous balloon, nine (45.0%) surgical) and eight (28.6%) did not require any treatment at birth, but, of these, five (62.5%) underwent surgical valvuloplasty between day 26 and day 1200 of age. Eleven (39.3%) of the infants with BVC at birth required a second intervention and four (14.3%) of them required a third intervention. Two (7.1%) infants who entered the BVC pathway at birth underwent conversion to univentricular circulation (UVC). None of the surviving children with BVC developed pulmonary hypertension. The overall survival rate in those with BVC at birth was 22/28 (78.6%) at a median (range) follow-up of 23.3 (2.0-112.6) months. Ten of the 58 (17.2%) patients had UVC at birth. Among these, six (60.0%) received compassionate care from birth and four (40.0%) underwent surgery. Three of the 10 patients who were UVC at birth were still alive at the latest follow-up assessment, at a median (range) gestational age of 24.3 (8.3-48.7) months. CONCLUSIONS: FAV for critical AS led to increase of antegrade aortic flow in 86.2% of fetuses, with BVC being achieved in 48.3% (73.7% of the liveborn cases). Among patients with BVC at birth, the rate of reintervention was high, but 78.6% of these children were alive at the latest evaluation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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PMMA is often considered as a calibration material for experimental benches dedicated to viscoelasticity investigation. Nevertheless, regarding literature, data concerning attenuation coefficients and quality factors are essentially available in the MHz frequency range and results in the low-frequency range are scarce and scattered. In this communication, thanks to the use of high-frequency ultrasonic spectroscopy between 2 and 8 MHz in the range 6 °C - 45 °C, Time-Temperature Superposition principle and Resonant Ultrasonic Spectroscopy (RUS), we show that both longitudinal and shear quality factors of PMMA decrease considerably for low frequencies (
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OBJECTIVES: Outcome of common arterial trunk (CAT) depends mainly on truncal valve function, presence of coronary artery abnormalities and presence of interrupted aortic arch. The main objective of this study was to evaluate the accuracy of prenatal diagnosis of CAT by analyzing prenatal vs postnatal assessment of: (1) anatomic subtypes and (2) truncal valve function. The secondary objective was to assess the potential impact of prenatal diagnosis of CAT on postnatal mortality and morbidity by comparing prenatally vs postnatally diagnosed patients. METHODS: This was a retrospective analysis of all CAT patients diagnosed either prenatally, with postnatal or fetopsy confirmation, or postnatally, from 2011 to 2019 in a single tertiary center. Cohen's kappa statistic was used to evaluate agreement between pre- and postnatal assessment of anatomic subtypes according to Van Praagh and of truncal valve function. Mortality and morbidity variables were compared between prenatally vs postnatally diagnosed CAT patients. RESULTS: A total of 84 patients (62 liveborn with prenatal diagnosis, 16 liveborn with postnatal diagnosis and six terminations of pregnancy with fetopsy) met the inclusion criteria. The accuracy of prenatal diagnosis of CAT anatomic subtype was 80.3%, and prenatal and postnatal concordance for subtype diagnosis was only moderate (κ = 0.43), with no patient with CAT Type A3 (0/4) and only half of patients with CAT Type A4 (8/17) being diagnosed prenatally. Fetal evaluation of truncal valve function underestimated the presence (no agreement; κ = 0.09) and severity (slight agreement; κ = 0.19) of insufficiency. However, four of five cases of postnatally confirmed significant truncal valve stenosis were diagnosed prenatally, with fair agreement for both presence and severity of stenosis (κ = 0.38 and 0.24, respectively). Mortality was comparable in patients with and those without prenatal diagnosis (log-rank P = 0.87). CAT patients with fetal diagnosis underwent earlier intervention (P < 0.001), had shorter intubation time (P = 0.047) and shorter global hospital stay (P = 0.01). CONCLUSIONS: The accuracy of prenatal diagnosis of CAT is insufficient to tailor neonatal management and to predict outcome. Fetal assessment of truncal valve dysfunction appears unreliable due to perinatal transition. Improvement is necessary in the fetal diagnosis of anatomic subtypes of CAT requiring postnatal prostaglandin infusion. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Truncus Arteriosus, Persistent , Constriction, Pathologic , Female , Heart Defects, Congenital , Humans , Pregnancy , Prenatal Diagnosis , Retrospective Studies , Ultrasonography, PrenatalABSTRACT
As cancers develop, transformed cells hijack various host mechanisms and manipulate them to create a dynamic tumor microenvironment, which supports tumor growth. This protumorigenic microenvironment is made up of many different cell types, including transformed cells, fibroblasts, inflammatory cells, and endothelial cells, the interactions of which have been shown to play a role in sustaining tumor growth. Multiple reports implicate the inflammatory cells of the tumor microenvironment as having both pro- and antitumorigenic roles, the balance of which is vital for the progression of the tumor, and while our understanding of established cancers has vastly increased since the turn of the 21st Century, our knowledge of these cellular interactions at the earliest stages of cancer initiation and development remains relatively limited. This is largely due to difficulties in monitoring these processes in vivo and in real time. Since the late nineties, the zebrafish (Danio rerio) has emerged as a vital model organism, allowing studies of previously unattainable stages of tumor initiation in a vertebrate model system. Using genetic and live-imaging approaches, this model system can be used both independently to monitor stages of tumor progression from the earliest initiation stages and incorporated into previously established systems to investigate the interactions between cancer cells and the various cell types of the tumor microenvironment, including inflammatory cells. Here, we describe the use of an inducible KalTA4-ERT2/UAS expression system in zebrafish, which allows spatial and temporal control of preneoplastic cell (PNC) growth and monitoring of innate immune cells in response to the developing PNC microenvironment.
Subject(s)
Immunity, Innate , Molecular Imaging/methods , Neoplasms/immunology , Tumor Microenvironment/immunology , Animals , Animals, Genetically Modified , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Humans , Neoplasms/genetics , Neoplasms/pathology , ZebrafishABSTRACT
During a colloidal droplet evaporation, a sol-gel transition can be observed and is described by the desiccation time τD and the gelation time τG. These characteristic times, which can be linked to viscoelastic properties of the droplet and to its composition, are classically rated by analysis of mass droplet evolution during evaporation. Even if monitoring mass evolution versus time seems straightforward, this approach is very sensitive to environmental conditions (vibrations, air flow ) as mass has to be evaluated very accurately using ultra-sensitive weighing scales. In this study we investigated the potentialities of ultrasonic shear reflectometry to assess τD and τG in a simple and reliable manner. In order to validate this approach, our study has focused on blood droplets evaporation on which a great deal of work has recently been published. Desiccation and gelation times measured with shear ultrasonic reflectometry have been perfectly correlated to values obtained from mass versus time analysis. This ultrasonic method which is not very sensitive to environmental perturbations is therefore very interesting to monitor the drying of blood droplets in a simple manner and is more generally suitable for complex fluid droplets evaporation investigation.
Subject(s)
Blood Chemical Analysis , Ultrasonics , Blood , Chemical Phenomena , Desiccation , Humans , VibrationABSTRACT
OBJECTIVES: To report on a series of 10 fetuses with prenatally diagnosed isolated total anomalous pulmonary venous connection (TAPVC), focusing on echocardiographic features leading to diagnosis, assess accuracy of prenatal diagnosis and describe postnatal outcome. METHODS: In this review of our experience of prenatal diagnosis of isolated TAPVC, we analyzed retrospectively medical records and fetal echocardiography findings in all cases with prenatal diagnosis of isolated TAPVC delivered between 1 January 2001 and 1 October 2011 at a tertiary referral center, paying special attention to echocardiographic signs that led to referral. RESULTS: During the study period, 95 infants with isolated TAPVC were seen at the center. Initially, expert fetal echocardiography identified 14 fetuses with isolated TAPVC. Prenatal diagnosis was made at a mean gestational age of 31 (range, 25-37) weeks. Ten true-positive cases of TAPVC were confirmed after birth. The remaining four were considered false-positive cases: two had normal heart with left superior vena cava to coronary sinus, one had partial anomalous venous connection and one was lost to follow-up. Of the 85 diagnosed postnatally with TAPVC, only one had been seen prenatally by an expert cardiac sonographer. Echocardiographic signs leading to referral were related to pulmonary venous connection in half of the cases. Other suspected defects which led to referral were ostium prium atrial defect (n = 3), left-right asymmetry (n = 1), abnormal mitral valve (n = 1) and hepatic vascular malformation (n = 1). All infants with TAPVC underwent surgery. There was one postoperative death and nine survivors, with a mean follow-up of 31 (range, 2-104) months. CONCLUSION: Fetal diagnosis of isolated TAPVC is challenging even for experts. Echocardiographic anomalies may appear late in gestation. New tools should be proposed to identify abnormal venous drainage at the screening level.
Subject(s)
Echocardiography/methods , Fetal Diseases/diagnostic imaging , Heart Defects, Congenital/diagnostic imaging , Scimitar Syndrome/diagnostic imaging , Ultrasonography, Prenatal/methods , Female , Fetal Diseases/surgery , Heart Defects, Congenital/surgery , Humans , Pregnancy , Prenatal Diagnosis , Retrospective Studies , Scimitar Syndrome/surgery , Treatment OutcomeABSTRACT
The goal of this paper is to propose an experimental method allowing the identification of the complete elastic tensor of anisotropic biological materials such as wood using only one sample. To do so, two complementary methods are used. First, the wood eigen-directions are defined from a sample of spherical shape that is then cut into a cube in a way to perform resonant ultrasound spectroscopy (RUS). The method is successfully applied on a reference beech sample with known orthotropic directions. A comparison of the identified elastic constants with those from the literature and some inferred from ultrasonic transmission measurements is given.
ABSTRACT
Kawasaki disease (KD) is an acute systemic vasculitis syndrome occurring mostly in children younger than 5 years of age. Especially young infants (<1 year) have an increased risk of coronary artery lesions (CAL). Whereas the etiology of KD is still unknown, progress in treatment during its acute phase has decreased the incidence of CAL from 25-30% to 3-5%. In "atypical KD", the clinical picture is dominated by an unusual symptom as seizure, bloody diarrhea, compressive cervical adenopathy, nephrotic syndrome or hyponatremia. To make a diagnosis in case of "incomplete KD", the supplementary criteria (clinical and biological) suggested by the American Heart Association can be helpful. Once the diagnosis established, the treatment of choice is the intravenous administration of immunoglobulin associated to aspirin at anti-inflammatory dose. However, some patients remain feverish within 36 hours following the end of immunoglobulin administration. This treatment resistance seems increasing in some regions of the globe and can touch up 20% of patients. The unsatisfactory answer to the initial treatment is associated to a higher risk of CAL. Predictive criteria of resistance have been identified and allow to strengthen the medical treatment with a second administration of immunoglobulins. Moreover, methylprednisolone pulse therapy and tumor necrosis factor-alpha blockade (infliximab) appear to be interesting therapeutic options in the future. At last, other treatments have not been the object of controlled studies yet but are alternatives in refractory forms e.g. cytotoxic agents (cyclosporine A, cyclophosphamide, methotrexate), plasmapheresis, plasma exchange or abciximab, especially in patients with aneurysms. Sclerotic vascular changes are often observed in post-Kawasaki disease patients, including those without coronary lesions during the acute phase. Indeed, endothelial dysfunction and risk factors for the development of atherosclerosis, such as dyslipidemia, decreased vascular elasticity, increased C-reactive protein, oxidative stress, and inflammatory cytokines, are known to be present in the late phase of KD. However, it is not clearly established that the survivors of KD carry a higher risk of coronary disease. The epidemiological studies of the next decade should give clearer answers as far as these patients henceforth achieved the age of the atherosclerosis. In conclusion, the diagnosis of KD imposes a strict supervision by a pediatric cardiologist initially. The follow-up is organized according to the existence or non-existence of coronary artery lesions. Late complications as stenosis or coronary thrombosis can occur but remain rare. Thus, it is necessary to be reassuring with the parents, especially for those whose children had no or regressive CAL, while recommending a prevention of the cardiovascular risk factors in the adulthood.
Subject(s)
Mucocutaneous Lymph Node Syndrome/diagnosis , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal/therapeutic use , Aspirin/therapeutic use , Child, Preschool , Combined Modality Therapy , Controlled Clinical Trials as Topic , Coronary Artery Disease/diagnosis , Coronary Artery Disease/drug therapy , Diagnosis, Differential , Humans , Immunoglobulins/therapeutic use , Infant , Infliximab , Methylprednisolone/therapeutic use , Mucocutaneous Lymph Node Syndrome/drug therapy , Prognosis , Pulse Therapy, Drug , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Costello syndrome is a rare association of symptoms caused by de novo germline mutations of the HRAS oncogene interfering in the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Mutations in this pathway are also responsible for Noonan syndrome and the related cardiofaciocutaneous syndrome (CFC) as well as LEOPARD syndrome. The 4 syndromes share phenotypic resemblances concerning patients' morphology but also regarding associated cardiac disease, namely hypertrophic cardiomyopathy, pulmonary stenosis, and atrial septal defect. The electrocardiogram often shows an upper deviation of the QRS axis. Arrhythmias are rare but, if present, are particularly typical of CS. We describe herein two newborn infants with Costello syndrome revealed by atrial tachycardia associated with characteristic morphological and cardiac features of syndromes related to mutations in the RAS/MAPK pathway.
Subject(s)
Abnormalities, Multiple/diagnosis , Costello Syndrome/diagnosis , Tachycardia, Paroxysmal/diagnosis , Abnormalities, Multiple/genetics , Biomarkers/blood , Costello Syndrome/complications , Costello Syndrome/genetics , Diagnosis, Differential , Female , Humans , Infant, Newborn , Mitogen-Activated Protein Kinases/genetics , Mutation , Phenotype , Signal Transduction , Tachycardia, Paroxysmal/etiology , Tachycardia, Paroxysmal/genetics , ras Proteins/geneticsABSTRACT
Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, the protein that plays a key mechanical role in maintaining muscle membrane integrity. One of the major consequences of dystrophin deficiency is the degeneration of muscle fibres, with a progressive loss in muscle strength. The objective of this research was to find an ultrasonic parameter sensitive to DMD, which could give relevant information related to microstructure if compared to traditional investigations such as morphometrical analysis. This "in vitro" study focused on the Mdx mouse model and investigated the potential differences between wild-type and dystrophin-deficient mice diaphragms. Using a 50MHz ultrasonic sensor built in our group, we recorded an increase in ultrasonic wave attenuation in the dystrophin-deficient samples in comparison with normal muscles. A correlation between attenuation, mouse age and the percentage of non-muscular proportion in muscle was observed. As Mdx mouse is the best animal model for DMD and reproduces the degenerative pattern observed in human DMD muscles, this approach could be a powerful tool for in vitro DMD investigation and, more generally, for the characterisation of muscle properties.
Subject(s)
Muscular Dystrophy, Animal/diagnostic imaging , Muscular Dystrophy, Duchenne/diagnostic imaging , Animals , Disease Models, Animal , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Muscle, Skeletal/diagnostic imaging , UltrasonographyABSTRACT
In this work, we propose a study dedicated to the influence of the delay line nature in transverse ultrasonic sensors, dedicated to dynamic high frequency elastic moduli of viscoelastic materials estimation. In literature, these shear ultrasonic rheometers are using delay lines in glass or quartz and normal or oblique incidence of ultrasonic rays. The oblique incidence is used in order to improve the sensitivity of the measurements. We theoretically demonstrate in this work that the use of delay lines in polymers is recommended to improve the sensitivity. Due to modifications, performed on a 10 MHz commercial ultrasonic sensor, we experimentally show on glycerin (which is a Newtonian material) that it is possible to multiply by a factor 10 the sensitivity; compared to delay lines in quartz using a normal incidence of rays. Hence, we overpass the accuracy of the oblique incidence approach with a simpler experimental setup.
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Dynamic viscoelastic properties (G' and G''), ultrasonic shear velocity and attenuation were measured for aqueous solutions of sorbitol at 5 MHz. For pure sorbitol, the shear ultrasonic velocity reached 1470 ms(-1) with a density of 1500 kgm(-3), consequently leading to a high acoustical impedance compared with "classical" polymers (polystyrene, nylon, polyethylene, Teflon, etc.). We demonstrate that this surprisingly high shear ultrasonic velocity for a viscoelastic material was due to the fact that the glass transition begins at a concentration above 85% of sorbitol in water. Hence, pure sorbitol is an ideal coupling material for high frequency shear experiments.
Subject(s)
Materials Testing/methods , Models, Chemical , Nephelometry and Turbidimetry/methods , Sorbitol/chemistry , Ultrasonography/methods , Water/chemistry , Computer Simulation , Elastic Modulus , Light , Phase Transition , Scattering, Radiation , Shear Strength , Solutions , Sorbitol/analysis , Viscosity , Water/analysisABSTRACT
Ultrasonic longitudinal velocity and attenuation were measured for aqueous solutions of sorbitol at approximately 5 MHz. For pure sorbitol, the ultrasonic velocity reached 3200 m s(-1), consequently leading to a high acoustical impedance (around 5 x 10(6) Rayleigh) and good matching between the ultrasonic transducers and material samples.
Subject(s)
Sorbitol/chemistry , Ultrasonics , Water/chemistry , Absorption , Signal Processing, Computer-Assisted , SolutionsABSTRACT
A pulse-echo ultrasonic method is presented to measure elastic parameter variations during thermal loading with high accuracy. Using a dry coupling configuration dedicated to high temperature investigation, this technique has been applied on 6061-T6 aluminium samples up to 220 degrees C. Experimental settings are described to assess the measurement reproducibility estimated at a value of 0.2%. Consequently, the anisotropy of this aluminium between the rolling direction and two orthogonal axes has been clearly detected and also measured versus temperature. As regards the temperature dependence of these elastic parameters, these results are compared with the estimations of the Young's modulus obtained during mechanical tests in conditions of low cycle fatigue (LCF). The same linear variation versus temperature is found but with a shift of 7GPa. This difference has been classically attributed to systematic experimental error sources and to the distinction existing between dynamic and static elastic modulus.
Subject(s)
Alloys , Materials Testing/methods , Ultrasonics , Aluminum , Anisotropy , Elasticity , TemperatureABSTRACT
The macroscopic elastic properties of two composites (Duralumin/air and Duralumin/tungsten carbide (WC)) have been calculated using periodical homogenisation methods and the elastic properties of each phase (measured by high frequency acoustic microscopy). In order to check the validity of such an approach, acoustical resonant spectroscopy has also been applied. Thanks to the comparison between the resonant frequencies predicted and measured, two major conclusions have been obtained: the homogenisation method is very accurate for the composite Duralumin/air, but not for the Duralumin/WC sample: the experimental results are not in very good agreement with the simulation. This result can be then explained by the major role of interfacial state between Duralumin and tungsten carbide.
Subject(s)
Manufactured Materials/analysis , Materials Testing/methods , Microscopy, Acoustic/methods , Models, Chemical , Spectrum Analysis/methods , Computer Simulation , ElasticityABSTRACT
Pseudomonas aeruginosa PAO1 became considerably more sensitive to the action of ampicillin when grown in the presence of certain phospholipids. Only phospholipids capable of forming lipid bilayers or micelles proved to be capable of enhancing ampicillin activity. Of the phospholipids tested, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphate, also called monopalmitoylphosphatidic acid (MPPA), was the best enhancer. In the absence of MPPA, the MIC and MBC of ampicillin for P. aeruginosa PAO1 were 1 and 2 g/L, respectively. In the presence of MPPA, the MIC and MBC were 20 and 40 mg/L, respectively. MPPA was shown to enhance ampicillin activity by binding both Ca(2+) and Mg(2+), suggesting that the mechanism of enhancement is similar to that previously reported for Ca(2+) and Mg(2+) chelators. Surprisingly, MPPA by itself slowed the growth of four mucoid multiply antibiotic-resistant strains of P. aeruginosa recently isolated from the sputum of cystic fibrosis patients, and enhanced their sensitivity to piperacillin. It also increased the sensitivity of two ceftazidime-resistant P. aeruginosa cystic fibrosis strains to ceftazidime.
Subject(s)
Ampicillin/pharmacology , Penicillins/pharmacology , Phospholipids/pharmacology , Pseudomonas aeruginosa/drug effects , Ampicillin/metabolism , Anti-Bacterial Agents/pharmacology , Calcium/metabolism , Culture Media , Cystic Fibrosis/microbiology , Detergents/pharmacology , Environmental Microbiology , Fatty Acids/metabolism , Fatty Acids/pharmacology , Humans , Magnesium/metabolism , Microbial Sensitivity Tests , Penicillins/metabolism , Phosphatidylserines/metabolism , Phosphatidylserines/pharmacology , Phospholipids/metabolism , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/growth & developmentABSTRACT
A minitransposon mutant of Salmonella enterica serovar Typhimurium SR-11, SR-11 Fad(-), is unable to utilize gluconeogenic substrates as carbon sources and is avirulent and immunogenic when administered perorally to BALB/c mice (M. J. Utley et al., FEMS Microbiol. Lett., 163:129-134, 1998). Here, evidence is presented that the mutation in SR-11 Fad(-) that renders the strain avirulent is in the cra gene, which encodes the Cra protein, a regulator of central carbon metabolism.
Subject(s)
Bacterial Proteins/genetics , Genes, Bacterial , Repressor Proteins/genetics , Salmonella typhimurium/metabolism , Salmonella typhimurium/pathogenicity , Animals , Carbohydrate Metabolism , Citric Acid Cycle , Intestines/microbiology , Macrophages, Peritoneal/microbiology , Mice , Mice, Inbred BALB C , Mucus/microbiology , Mutagenesis, Insertional , Salmonella typhimurium/genetics , SerotypingABSTRACT
CpG island hypermethylation is a frequent epigenetic event in cancer. We have recently developed an array-based method, called differential methylation hybridization (DMH), allowing for a genome-wide screening of CpG island hypermethylation in breast cancer cell lines (T. H-M. Huang et al., Hum. Mol. Genet., 8: 459-470, 1999). In the present study, DMH was applied to screen 28 paired primary breast tumor and normal samples and to determine whether patterns of specific epigenetic alterations correlate with pathological parameters in the patients analyzed. Amplicons, representing a pool of methylated CpG DNA derived from these samples, were used as hybridization probes in an array panel containing 1104 CpG island tags. Close to 9% of these tags exhibited extensive hypermethylation in the majority of breast tumors relative to their normal controls, whereas others had little or no detectable changes. Pattern analysis in a subset of CpG island tags revealed that CpG island hypermethylation is associated with histological grades of breast tumors. Poorly differentiated tumors appeared to exhibit more hypermethylated CpG islands than their moderately or well-differentiated counterparts (P = 0.041). This early finding lays the groundwork for a population-based DMH study and demonstrates the need to develop a database for examining large-scale methylation data and for associating specific epigenetic signatures with clinical parameters in breast cancer.
Subject(s)
Breast Neoplasms/genetics , CpG Islands/genetics , Oligonucleotide Array Sequence Analysis/methods , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , DNA Methylation , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Female , Humans , Middle AgedABSTRACT
We examined the methylation status of the transcribed domain of ribosomal DNA (rDNA) in 58 patients with breast cancer. The mean percent of methylation was significantly higher in breast tumours than that of normal control samples (P < 0.0001). This increased rDNA methylation was associated with oestrogen receptor non-expression (P < 0.0273) and with moderately or poorly differentiated tumours as compared to well differentiated tumours (P < 0.0475). Our results suggest that rDNA can be a useful marker for monitoring aberrant methylation during breast tumour progression.
Subject(s)
Breast Neoplasms/metabolism , DNA Methylation , DNA, Ribosomal/metabolism , Adult , Aged , Blotting, Southern , Humans , Middle AgedABSTRACT
CpG island hypermethylation is known to be associated with transcriptional silencing of tumor suppressor genes in neoplasia. We have previously detected aberrantly methylated sites in the first intron of the Wilms' tumor suppressor (WT1) gene in breast cancer. In the present study, we extended the investigation to a CpG island located in the promoter and first exon regions of WT1. Methylation of this CpG island was found to be extensive in MCF-7 and MDA-MB-231 breast cancer cells, as well as in 25% (five of 20 patients) of primary breast tumors. While levels of the known 3.0-kb WT1 mRNAs were decreased or not detected in these cell lines, the expression could be partially restored following treatment with a demethylation agent, 5-aza-2'-deoxycytidine. Surprisingly, a novel 2.5-kb WT1 transcript was expressed at high levels in both untreated and treated MDA-MB-231 cells. This novel transcript was likely a WT1 variant missing the first exon, and therefore escaped the methylation control present in the normal transcript. Our study implicates the future need to investigate the significance of this aberrant transcript as well as the role of WT1 CpG island hypermethylation in breast neoplasia.