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1.
Background
The putative promoter of the holocarboxylase synthetase (HLCS) gene on chromosome 21 is hypermethylated in placental tissues and could be detected as a fetal-specific DNA marker in maternal plasma. Detection of fetal trisomy 21 (T21) has been demonstrated by an epigenetic-genetic chromosome dosage approach where the amount of hypermethylated HLCS in maternal plasma is normalized using a fetal genetic marker on the Y chromosome as a chromosome dosage reference marker. We explore if this method can be applied on both male and female fetuses with the use of a paternally-inherited fetal single nucleotide polymorphism (SNP) allele on a reference chromosome for chromosome dosage normalization.Methodology
We quantified hypermethylated HLCS molecules using methylation-sensitive restriction endonuclease digestion followed by real-time or digital PCR analyses. For chromosome dosage analysis, we compared the amount of digestion-resistant HLCS to that of a SNP allele (rs6636, a C/G SNP) that the fetus has inherited from the father but absent in the pregnant mother.Principal Findings
Using a fetal-specific SNP allele on a reference chromosome, we analyzed 20 euploid and nine T21 placental tissue samples. All samples with the fetal-specific C allele were correctly classified. One sample from each of the euploid and T21 groups were misclassified when the fetal-specific G allele was used as the reference marker. We then analyzed 33 euploid and 14 T21 maternal plasma samples. All but one sample from each of the euploid and T21 groups were correctly classified using the fetal-specific C allele, while correct classification was achieved for all samples using the fetal-specific G allele as the reference marker.Conclusions
As a proof-of-concept study, we have demonstrated that the epigenetic-genetic chromosome dosage approach can be applied to the prenatal diagnosis of trisomy 21 for both male and female fetuses. 相似文献2.
Background
Quantification of cell-free fetal DNA by methylation-based DNA discrimination has been used in non-invasive prenatal testing of fetal chromosomal aneuploidy. The maspin (Serpin peptidase inhibitor, clade B (ovalbumin), member 5; SERPINB5) gene, located on chromosome 18q21.33, is hypomethylated in the placenta and completely methylated in maternal blood cells. The objective of this study was to evaluate the accuracy of non-invasive detection of fetal trisomy 18 using the unmethylated-maspin (U-maspin) gene as a cell-free fetal DNA marker and the methylated-maspin (M-maspin) gene as a cell-free total DNA marker in the first trimester of pregnancy.Methodology/Principal Findings
A nested case-control study was conducted using maternal plasma collected from 66 pregnant women, 11 carrying fetuses with trisomy 18 and 55 carrying normal fetuses. Median U-maspin concentrations were significantly elevated in women with trisomy 18 fetuses compared with controls (27.2 vs. 6.7 copies/mL; P<0.001). Median M-maspin concentrations were also significantly higher in women with trisomy 18 fetuses than in controls (96.9 vs. 19.5 copies/mL, P<0.001). The specificities of U-maspin and M-maspin concentrations for non-invasive fetal trisomy 18 detection were 96.4% and 74.5%, respectively, with a sensitivity of 90.9%.Conclusions
Our results suggest that U-maspin and M-maspin concentrations may be useful as potential biomarkers for non-invasive detection of fetal trisomy 18 in the first trimester of pregnancy, irrespective of the sex and genetic variations of the fetus. 相似文献3.
Megan P. Hall Matthew Hill Bernhard Zimmermann Styrmir Sigurjonsson Margaret Westemeyer Jennifer Saucier Zachary Demko Matthew Rabinowitz 《PloS one》2014,9(5)
Purpose
To determine how a single nucleotide polymorphism (SNP)- and informatics-based non-invasive prenatal aneuploidy test performs in detecting trisomy 13.Methods
Seventeen trisomy 13 and 51 age-matched euploid samples, randomly selected from a larger cohort, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex polymerase chain reaction assay that interrogated 19,488 SNPs covering chromosomes 13, 18, 21, X, and Y, and sequenced. Analysis and copy number identification involved a Bayesian-based maximum likelihood statistical method that generated chromosome- and sample-specific calculated accuracies.Results
Of the samples that passed a stringent DNA quality threshold (94.1%), the algorithm correctly identified 15/15 trisomy 13 and 49/49 euploid samples, for 320/320 correct copy number calls.Conclusions
This informatics- and SNP-based method accurately detects trisomy 13-affected fetuses non-invasively and with high calculated accuracy. 相似文献4.
Lim JH Kim SY Park SY Lee SY Kim MJ Han YJ Lee SW Chung JH Kim MY Yang JH Ryu HM 《PloS one》2011,6(11):e27709
Background
Down syndrome (DS) is the most common known aneuploidy, caused by an extra copy of all or part of chromosome 21. Fetal-specific epigenetic markers have been investigated for non-invasive prenatal detection of fetal DS. The phosphodiesterases gene, PDE9A, located on chromosome 21q22.3, is completely methylated in blood (M-PDE9A) and unmethylated in the placenta (U-PDE9A). Therefore, we estimated the accuracy of non-invasive fetal DS detection during the first trimester of pregnancy using this tissue-specific epigenetic characteristic of PDE9A.Methodology/Principal Findings
A nested, case-control study was conducted using maternal plasma samples collected from 108 pregnant women carrying 18 DS and 90 normal fetuses (each case was matched with 5 controls according to gestational weeks at blood sampling). All pregnancies were singletons at or before 12 weeks of gestation between October 2008 and May 2009. The maternal plasma levels of M-PDE9A and U-PDE9A were measured by quantitative methylation-specific polymerase chain reaction. M-PDE9A and U-PDE9A levels were obtained in all samples and did not differ between male and female fetuses. M-PDE9A levels did not differ between the DS cases and controls (1854.3 vs 2004.5 copies/mL; P = 0.928). U-PDE9A levels were significantly elevated in women with DS fetuses compared with controls (356.8 vs 194.7 copies/mL, P<0.001). The sensitivities of U-PDE9A level and the unmethylation index of PDE9A for non-invasive fetal DS detection were 77.8% and 83.3%, respectively, with a 5% false-positive rate. In the risk assessment for fetal DS, the adjusted odds ratios of U-PDE9A level and UI were 46.2 [95% confidence interval: 7.8–151.6] and 63.7 [95% confidence interval: 23.2–206.7], respectively.Conclusions
Our findings suggest that U-PDE9A level and the unmethylation index of PDE9A may be useful biomarkers for non-invasive fetal DS detection during the first trimester of pregnancy, regardless of fetal gender. 相似文献5.
Maternal serum cell-free fetal DNA levels are increased in cases of trisomy 13 but not trisomy 18 总被引:16,自引:0,他引:16
Wataganara T LeShane ES Farina A Messerlian GM Lee T Canick JA Bianchi DW 《Human genetics》2003,112(2):204-208
Cell-free fetal DNA in the maternal circulation is a potential noninvasive marker for fetal aneuploidies. In previous studies with Y DNA as a fetal-specific marker, levels of circulating fetal DNA were shown to be elevated in women carrying trisomy 21 fetuses. The goal of this study was to determine whether cell-free fetal DNA levels in the serum of pregnant women carrying fetuses with trisomies 13 or 18 are also elevated. Archived maternal serum samples from five cases of male trisomy 13 and five cases of male trisomy 18 were studied. Each case was matched for fetal gender, gestational age, and duration of freezer storage to four or five control serum samples presumed to be euploid after newborn medical record review. Real-time quantitative polymerase chain reaction amplification of DYS1 was performed to measure the amount of male fetal DNA present. Unadjusted median serum fetal DNA concentrations were 97.5 GE/ml (genomic equivalents per milliliter; 29.2-187.0) for the trisomy 13 cases, 31.5 GE/ml (18.6-77.6) for the trisomy 18 cases, and 40.3 GE/ml (3.7-127.4) for the controls. Fetal DNA levels in trisomy 13 cases were significantly elevated ( P=0.016) by analysis of variance of the ranks of values within each matched set. In contrast, fetal DNA levels in trisomy 18 cases were no different from the controls ( P=0.244). Second trimester maternal serum analytes currently used in screening do not identify fetuses at high risk for trisomy 13. Fetal DNA may facilitate noninvasive screening for trisomy 13 provided that a gender-independent fetal DNA marker can be developed. 相似文献
6.
Jessica M. E. van den Oever Sahila Balkassmi Tim Segboer E. Joanne Verweij Pieter A. van der Velden Dick Oepkes Egbert Bakker Elles M. J. Boon 《PloS one》2013,8(12)
Objectives
RASSF1A has been described to be differentially methylated between fetal and maternal DNA and can therefore be used as a universal sex-independent marker to confirm the presence of fetal sequences in maternal plasma. However, this requires highly sensitive methods. We have previously shown that Pyrophosphorolysis-activated Polymerization (PAP) is a highly sensitive technique that can be used in noninvasive prenatal diagnosis. In this study, we have used PAP in combination with bisulfite conversion to develop a new universal methylation-based assay for the detection of fetal methylated RASSF1A sequences in maternal plasma.Methods
Bisulfite sequencing was performed on maternal genomic (g)DNA and fetal gDNA from chorionic villi to determine differentially methylated regions in the RASSF1A gene using bisulfite specific PCR primers. Methylation specific primers for PAP were designed for the detection of fetal methylated RASSF1A sequences after bisulfite conversion and validated.Results
Serial dilutions of fetal gDNA in a background of maternal gDNA show a relative percentage of ∼3% can be detected using this assay. Furthermore, fetal methylated RASSF1A sequences were detected both retrospectively as well as prospectively in all maternal plasma samples tested (n = 71). No methylated RASSF1A specific bands were observed in corresponding maternal gDNA. Specificity was further determined by testing anonymized plasma from non-pregnant females (n = 24) and males (n = 21). Also, no methylated RASSF1A sequences were detected here, showing this assay is very specific for methylated fetal DNA. Combining all samples and controls, we obtain an overall sensitivity and specificity of 100% (95% CI 98.4%–100%).Conclusions
Our data demonstrate that using a combination of bisulfite conversion and PAP fetal methylated RASSF1A sequences can be detected with extreme sensitivity in a universal and sex-independent manner. Therefore, this assay could be of great value as an addition to current techniques used in noninvasive prenatal diagnostics. 相似文献7.
Ji Hyae Lim Da Eun Lee So Yeon Park Do Jin Kim Hyun Kyong Ahn You Jung Han Moon Young Kim Hyun Mee Ryu 《BMC medical genomics》2014,7(1):1-11
Background
Non-invasive prenatal testing of trisomy 21 (T21) is being actively investigated using fetal-specific epigenetic markers (EPs) that are present in maternal plasma. Recently, 12 EPs on chromosome 21 were identified based on tissue-specific epigenetic characteristics between placenta and blood, and demonstrated excellent clinical performance in the non-invasive detection of fetal T21. However, the disease-specific epigenetic characteristics of the EPs have not been established. Therefore, we validated the disease-specific epigenetic characteristics of these EPs for use in non-invasive detection of fetal T21.Methods
We performed a high-resolution tiling array analysis of human chromosome 21 using a methyl-CpG binding domain-based protein (MBD) method with whole blood samples from non-pregnant normal women, whole blood samples from pregnant normal women, placenta samples of normal fetuses, and placenta samples of T21 fetuses. Tiling array results were validated by bisulfite direct sequencing and qPCR.Results
Among 12 EPs, only four EPs were confirmed to be hypermethylated in normal placenta and hypomethylated in blood. One of these four showed a severe discrepancy in the methylation patterns of T21 placenta samples, and another was located within a region of copy number variations. Thus, two EPs were confirmed to be potential fetal-specific markers based on their disease-specific epigenetic characteristics. The array results of these EPs were consisted with the results obtained by bisulfite direct sequencing and qPCR. Moreover, the two EPs were detected in maternal plasma.Conclusions
We validated that two EPs have the potential to be fetal-specific EPs which is consistent with their disease-specific epigenetic characteristics. The findings of this study suggest that disease-specific epigenetic characteristics should be considered in the development of fetal-specific EPs for non-invasive prenatal testing of T21. 相似文献8.
9.
Young Joo Jeon Yulin Zhou Yihan Li Qiwei Guo Jinchun Chen Shengmao Quan Ahong Zhang Hailing Zheng Xingqiang Zhu Jin Lin Huan Xu Ayang Wu Sin-Gi Park Byung Chul Kim Hee Jae Joo Hongliang Chen Jong Bhak 《PloS one》2014,9(10)
Objective
Recent non-invasive prenatal testing (NIPT) technologies are based on next-generation sequencing (NGS). NGS allows rapid and effective clinical diagnoses to be determined with two common sequencing systems: Illumina and Ion Torrent platforms. The majority of NIPT technology is associated with Illumina platform. We investigated whether fetal trisomy 18 and 21 were sensitively and specifically detectable by semiconductor sequencer: Ion Proton.Methods
From March 2012 to October 2013, we enrolled 155 pregnant women with fetuses who were diagnosed as high risk of fetal defects at Xiamen Maternal & Child Health Care Hospital (Xiamen, Fujian, China). Adapter-ligated DNA libraries were analyzed by the Ion Proton™ System (Life Technologies, Grand Island, NY, USA) with an average 0.3× sequencing coverage per nucleotide. Average total raw reads per sample was 6.5 million and mean rate of uniquely mapped reads was 59.0%. The results of this study were derived from BWA mapping. Z-score was used for fetal trisomy 18 and 21 detection.Results
Interactive dot diagrams showed the minimal z-score values to discriminate negative versus positive cases of fetal trisomy 18 and 21. For fetal trisomy 18, the minimal z-score value of 2.459 showed 100% positive predictive and negative predictive values. The minimal z-score of 2.566 was used to classify negative versus positive cases of fetal trisomy 21.Conclusion
These results provide the evidence that fetal trisomy 18 and 21 detection can be performed with semiconductor sequencer. Our data also suggest that a prospective study should be performed with a larger cohort of clinically diverse obstetrics patients. 相似文献10.
Jacob M?rup Schlütter Ida Kirkegaard Olav Bj?rn Petersen Nanna Larsen Britta Christensen David M. Hougaard Steen K?lvraa Niels Uldbjerg 《PloS one》2014,9(9)
Objective
To identify factors influencing the number of fetal cells in maternal blood.Methods
A total of 57 pregnant women at a gestational age of weeks 11–14 were included. The number of fetal cells in maternal blood was assessed in 30 ml of blood using specific markers for both enrichment and subsequent identification.Results
Participants carrying male fetuses had a higher median number of fetal cells in maternal blood than those carrying female fetuses (5 vs. 3, p = 0.04). Certain cytokines (RANTES, IL-2 and IL-5) were significantly associated with the number of fetal cells in maternal blood.Conclusion
The number of fetal cells in maternal blood is associated with certain cytokines and fetal gender. 相似文献11.
Background
Analysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders. True positive results rely on detection of the fetal target being analysed. No amplification of the target may be interpreted either as a true negative result or a false negative result due to the absence or very low levels of cffDNA. The hypermethylated RASSF1A promoter has been reported as a universal fetal marker to confirm the presence of cffDNA. Using methylation-sensitive restriction enzymes hypomethylated maternal sequences are digested leaving hypermethylated fetal sequences detectable. Complete digestion of maternal sequences is required to eliminate false positive results.Methods
cfDNA was extracted from maternal plasma (n = 90) and digested with methylation-sensitive and insensitive restriction enzymes. Analysis of RASSF1A, SRY and DYS14 was performed by real-time PCR.Results
Hypermethylated RASSF1A was amplified for 79 samples (88%) indicating the presence of cffDNA. SRY real time PCR results and fetal sex at delivery were 100% accurate. Eleven samples (12%) had no detectable hypermethylated RASSF1A and 10 of these (91%) had gestational ages less than 7 weeks 2 days. Six of these samples were male at delivery, five had inconclusive results for SRY analysis and one sample had no amplifiable SRY.Conclusion
Use of this assay for the detection of hypermethylated RASSF1A as a universal fetal marker has the potential to improve the diagnostic reliability of NIPD for fetal sex determination and single gene disorders. 相似文献12.
Xu-Ping Xu Hai-Yan Gan Fen-Xia Li Qi Tian Jun Zhang Rong-Liang Liang Ming Li Xue-Xi Yang Ying-Song Wu 《PloS one》2016,11(1)
Objective
The fraction of circulating cell-free fetal (cff) DNA in maternal plasma is a critical parameter for aneuploidy screening with non-invasive prenatal testing, especially for those samples located in equivocal zones. We developed an approach to quantify cff DNA fractions directly with sequencing data, and increased cff DNAs by optimizing library construction procedure.Methods
Artificial DNA mixture samples (360), with known cff DNA fractions, were used to develop a method to determine cff DNA fraction through calculating the proportion of Y chromosomal unique reads, with sequencing data generated by Ion Proton. To validate our method, we investigated cff DNA fractions of 2,063 pregnant women with fetuses who were diagnosed as high risk of fetal defects. The z-score was calculated to determine aneuploidies for chromosomes 21, 18 and 13. The relationships between z-score and parameters of pregnancies were also analyzed. To improve cff DNA fractions in our samples, two groups were established as follows: in group A, the large-size DNA fragments were removed, and in group B these were retained, during library construction.Results
A method to determine cff DNA fractions was successfully developed using 360 artificial mixture samples in which cff DNA fractions were known. A strong positive correlation was found between z-score and fetal DNA fraction in the artificial mixture samples of trisomy 21, 18 and 13, as well as in clinical maternal plasma samples. There was a positive correlation between gestational age and the cff DNA fraction in the clinical samples, but no correlation for maternal age. Moreover, increased fetal DNA fractions were found in group A compared to group B.Conclusion
A relatively accurate method was developed to determine the cff DNA fraction in maternal plasma. By optimizing, we can improve cff DNA fractions in sequencing samples, which may contribute to improvements in detection rate and reliability. 相似文献13.
Huijuan Ge Xuan Huang Xuchao Li Shengpei Chen Jing Zheng Haojun Jiang Chunlei Zhang Xiaoyu Pan Jing Guo Fang Chen Ning Chen Qun Fang Hui Jiang Wei Wang 《PloS one》2013,8(6)
Background
The discovery of cell free fetal DNA (cff-DNA) in maternal plasma has brought new insight for noninvasive prenatal diagnosis. Combining with the rapidly developed massively parallel sequencing technology, noninvasive prenatal detection of chromosome aneuploidy and single base variation has been successfully validated. However, few studies discussed the possibility of noninvasive pathogenic CNVs detection.Methodology/Principal Findings
A novel algorithm for noninvasive prenatal detection of fetal pathogenic CNVs was firstly tested in 5 pairs of parents with heterozygote α-thalassemia of Southeast Asian (SEA) deletion using target region capture sequencing for maternal plasma. Capture probes were designed for α-globin (HBA) and β-globin (HBB) gene, as well as 4,525 SNPs selected from 22 automatic chromosomes. Mixed adaptors with 384 different barcodes were employed to construct maternal plasma DNA library for massively parallel sequencing. The signal of fetal CNVs was calculated using the relative copy ratio (RCR) of maternal plasma combined with the analysis of R-score and L-score by comparing with normal control. With mean of 101.93× maternal plasma sequencing depth for the target region, the RCR value combined with further R-score and L-score analysis showed a possible homozygous deletion in the HBA gene region for one fetus, heterozygous deletion for two fetus and normal for the other two fetus, which was consistent with that of invasive prenatal diagnosis.Conclusions/Significance
Our study showed the feasibility to detect pathogenic CNVs using target region capture sequencing, which might greatly extend the scope of noninvasive prenatal diagnosis. 相似文献14.
Taylor J. Jensen Tricia Zwiefelhofer Roger C. Tim ?eljko D?akula Sung K. Kim Amin R. Mazloom Zhanyang Zhu John Tynan Tim Lu Graham McLennan Glenn E. Palomaki Jacob A. Canick Paul Oeth Cosmin Deciu Dirk van den Boom Mathias Ehrich 《PloS one》2013,8(3)
Background
Circulating cell-free (ccf) fetal DNA comprises 3–20% of all the cell-free DNA present in maternal plasma. Numerous research and clinical studies have described the analysis of ccf DNA using next generation sequencing for the detection of fetal aneuploidies with high sensitivity and specificity. We sought to extend the utility of this approach by assessing semi-automated library preparation, higher sample multiplexing during sequencing, and improved bioinformatic tools to enable a higher throughput, more efficient assay while maintaining or improving clinical performance.Methods
Whole blood (10mL) was collected from pregnant female donors and plasma separated using centrifugation. Ccf DNA was extracted using column-based methods. Libraries were prepared using an optimized semi-automated library preparation method and sequenced on an Illumina HiSeq2000 sequencer in a 12-plex format. Z-scores were calculated for affected chromosomes using a robust method after normalization and genomic segment filtering. Classification was based upon a standard normal transformed cutoff value of z = 3 for chromosome 21 and z = 3.95 for chromosomes 18 and 13.Results
Two parallel assay development studies using a total of more than 1900 ccf DNA samples were performed to evaluate the technical feasibility of automating library preparation and increasing the sample multiplexing level. These processes were subsequently combined and a study of 1587 samples was completed to verify the stability of the process-optimized assay. Finally, an unblinded clinical evaluation of 1269 euploid and aneuploid samples utilizing this high-throughput assay coupled to improved bioinformatic procedures was performed. We were able to correctly detect all aneuploid cases with extremely low false positive rates of 0.09%, <0.01%, and 0.08% for trisomies 21, 18, and 13, respectively.Conclusions
These data suggest that the developed laboratory methods in concert with improved bioinformatic approaches enable higher sample throughput while maintaining high classification accuracy. 相似文献15.
16.
Nancy B. Y. Tsui Peiyong Jiang Katherine C. K. Chow Xiaoxi Su Tak Y. Leung Hao Sun K. C. Allen Chan Rossa W. K. Chiu Y. M. Dennis Lo 《PloS one》2012,7(10)
Background
Fetal DNA in maternal urine, if present, would be a valuable source of fetal genetic material for noninvasive prenatal diagnosis. However, the existence of fetal DNA in maternal urine has remained controversial. The issue is due to the lack of appropriate technology to robustly detect the potentially highly degraded fetal DNA in maternal urine.Methodology
We have used massively parallel paired-end sequencing to investigate cell-free DNA molecules in maternal urine. Catheterized urine samples were collected from seven pregnant women during the third trimester of pregnancies. We detected fetal DNA by identifying sequenced reads that contained fetal-specific alleles of the single nucleotide polymorphisms. The sizes of individual urinary DNA fragments were deduced from the alignment positions of the paired reads. We measured the fractional fetal DNA concentration as well as the size distributions of fetal and maternal DNA in maternal urine.Principal Findings
Cell-free fetal DNA was detected in five of the seven maternal urine samples, with the fractional fetal DNA concentrations ranged from 1.92% to 4.73%. Fetal DNA became undetectable in maternal urine after delivery. The total urinary cell-free DNA molecules were less intact when compared with plasma DNA. Urinary fetal DNA fragments were very short, and the most dominant fetal sequences were between 29 bp and 45 bp in length.Conclusions
With the use of massively parallel sequencing, we have confirmed the existence of transrenal fetal DNA in maternal urine, and have shown that urinary fetal DNA was heavily degraded. 相似文献17.
Devasuda Anblagan Nia W. Jones Carolyn Costigan Alexander J. J. Parker Kirsty Allcock Rosanne Aleong Lucy H. Coyne Ruta Deshpande Nick Raine-Fenning George Bugg Neil Roberts Zdenka Pausova Tomá? Paus Penny A. Gowland 《PloS one》2013,8(7)
Objective
To study whether maternal cigarette smoking during pregnancy is associated with alterations in the growth of fetal lungs, kidneys, liver, brain, and placenta.Design
A case-control study, with operators performing the image analysis blinded.Setting
Study performed on a research-dedicated magnetic resonance imaging (MRI) scanner (1.5 T) with participants recruited from a large teaching hospital in the United Kingdom.Participants
A total of 26 pregnant women (13 current smokers, 13 non smokers) were recruited; 18 women (10 current smokers, 8 nonsmokers) returned for the second scan later in their pregnancy.Methods
Each fetus was scanned with MRI at 22–27 weeks and 33–38 weeks gestational age (GA).Main outcome measures
Images obtained with MRI were used to measure volumes of the fetal brain, kidneys, lungs, liver and overall fetal size, as well as placental volumes.Results
Exposed fetuses showed lower brain volumes, kidney volumes, and total fetal volumes, with this effect being greater at visit 2 than at visit 1 for brain and kidney volumes, and greater at visit 1 than at visit 2 for total fetal volume. Exposed fetuses also demonstrated lower lung volume and placental volume, and this effect was similar at both visits. No difference was found between the exposed and nonexposed fetuses with regards to liver volume.Conclusion
Magnetic resonance imaging has been used to show that maternal smoking is associated with reduced growth of fetal brain, lung and kidney; this effect persists even when the volumes are corrected for maternal education, gestational age, and fetal sex. As expected, the fetuses exposed to maternal smoking are smaller in size. Similarly, placental volumes are smaller in smoking versus nonsmoking pregnant women. 相似文献18.
Localized Fetomaternal Hyperglycemia: Spatial and Kinetic Definition by Positron Emission Tomography
Jianrong Yao Chunlin Wang Susan A. Walsh Shanming Hu Alexander B. Sawatzke Diana Dang Jeffrey L. Segar Laura L. B. Ponto John J. Sunderland Andrew W. Norris 《PloS one》2010,5(8)
Background
Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat.Methodology and Principal Findings
We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [18F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.9±0.1 and 2.8±0.3 fold under fasted and hyperinsulinemic conditions (p<10−11 n = 32-35 and p<10−12 n = 27–45) respectively. By contrast, centrally administered [3H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (103 mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained.Conclusions and Significance
This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health. 相似文献19.
Christopher P. E. Lange Mihaela Campan Toshinori Hinoue Roderick F. Schmitz Andrea E. van der Meulen-de Jong Hilde Slingerland Peter J. M. J. Kok Cornelis M. van Dijk Daniel J. Weisenberger Hui Shen Robertus A. E. M. Tollenaar Peter W. Laird 《PloS one》2012,7(11)
Background
There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer.Methodology/Principal Findings
We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection.Conclusions/Significance
Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing. 相似文献20.
Keishi Yamashita Mina Waraya Myoung Sook Kim David Sidransky Natsuya Katada Takeo Sato Takatoshi Nakamura Masahiko Watanabe 《PloS one》2014,9(12)