Mother Infant Research Institute

Boston, MA, United States

Mother Infant Research Institute

Boston, MA, United States
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Guedj F.,Mother Infant Research Institute | Pennings J.L.A.,National Institute for Public Health and the Environment RIVM | Wick H.C.,Tufts University | Bianchi D.W.,Mother Infant Research Institute
Brain Pathology | Year: 2014

We investigated gene expression and functional differences between Ts1Cje mice and wild-type (WT) littermates in adult cerebral cortex and hippocampus. These two brain regions are affected in people with Down syndrome, but have not been previously molecularly characterized in Ts1Cje mice. Total RNA was prepared from the brains of 8-10-week-old Ts1Cje mice (n = 6) and WT littermates (n = 5) and hybridized to Affymetrix 1.0 ST gene mouse arrays. Differentially regulated genes were identified and used to perform in silico functional analyses to better characterize dysregulated pathways in both brain regions. Hippocampus had more significantly differentially expressed genes compared with cortex (30 vs. 7 at a Benjamini-Hochberg false discovery rate of 20%). We identified novel genes that were differentially regulated in adult brains, including Cyb5r1, Fsbp, Vmn2r110, Snd1 and Zhx2. Functional analyses in Ts1Cje mice highlighted the importance of NFAT signaling, oxidative stress, neuroinflammation and olfactory perception via G-protein signaling. In a comparison of adult Ts1Cje and WT brains, we identified new genes and pathway differences in the cortex and hippocampus. Our analyses identified physiologically relevant pathways that can serve as targets for the development of future treatments to improve neurocognition in Down syndrome. © 2014 International Society of Neuropathology.

Bianchi D.W.,Mother Infant Research Institute | Chudova D.,Illumina | Sehnert A.J.,Illumina | Bhatt S.,Illumina | And 9 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignanciesmay explain results that are discordant with the fetal karyotype and improve maternal clinical care. OBJECTIVE To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. DESIGN, SETTING, AND PARTICIPANTS Case series identified from 125 426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation. EXPOSURES NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). MAIN OUTCOMES AND MEASURES Detailed genome-wide bioinformatics analysiswas performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort. RESULTS From a cohort of 125 426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95%CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. CONCLUSIONS AND RELEVANCE In this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research.

Vishwanathan R.,Tufts University | Kuchan M.J.,Abbott Laboratories | Sen S.,Mother Infant Research Institute | Johnson E.J.,Tufts University
Journal of Pediatric Gastroenterology and Nutrition | Year: 2014

Methods: Voluntarily donated brain tissues from 30 infants who died during the first 1.5 years of life were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank. Tissues (hippocampus and prefrontal, frontal, auditory, and occipital cortices) were extracted using standard lipid extraction procedures and analyzed using reverse-phase high-pressure liquid chromatography. Results: Lutein, zeaxanthin, cryptoxanthin, and β-carotene were the major carotenoids found in the infant brain tissues. Lutein was the predominant carotenoid accounting for 59% of total carotenoids. Preterm infants (n = 8) had significantly lower concentrations of lutein, zeaxanthin, and cryptoxanthin in their brain compared with term infants (n = 22) despite similarity in postmenstrual age. Among formula-fed infants, preterm infants (n=3) had lower concentrations of lutein and zeaxanthin compared with term infants (n=5). Brain lutein concentrations were not different between breast milk-fed (n=3) and formula-fed (n=5) term decedents. In contrast, term decedents with measurable brain cryptoxanthin, a carotenoid that is inherently low in formula, had higher brain lutein, suggesting that the type of feeding is an important determinant of brain lutein concentrations.Conclusions: These data reveal preferential accumulation and maintenance of lutein in the infant brain despite underrepresentation in the typical infant diet. Further investigation on the impact of lutein on neural development in preterm infants is warranted.Objectives: Lutein and zeaxanthin are dietary carotenoids that may influence visual and cognitive development. The objective of this study was to provide the first data on distribution of carotenoids in the infant brain and compare concentrations in preterm and term infants. Copyright © 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Sen S.,Tufts University | Sen S.,Mother Infant Research Institute | Sen S.,Tufts Medical Center | Iyer C.,Tufts Medical Center | Meydani S.N.,Tufts University
Journal of Perinatology | Year: 2014

Objective:Little is known about the effect of obesity on inflammatory status in pregnant women. The objective of this study was to determine the effect of obesity on markers of inflammation, oxidative stress and micronutrient status in obese pregnant women and their infants compared with lean controls (Lc).Study Design:This was a prospective case-control study. A total of 15 obese (Ob; body mass index (BMI) >30 kg m-2) and 15 lean (BMI 18-25 kg m-2) women were recruited based on prepregnancy BMI. Vitamins A, B6, C, E and 25-hydroxyvitamin D (25(OH)D), zinc, red blood cell (RBC) folate, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α and oxidized and reduced glutathione were measured from maternal blood between 24 and 28 weeks of gestation. Vitamins A, B 6, C and E, 25(OH)D, zinc, red blood cell folate, CRP and IL-6 were measured from cord blood at delivery.Result:Ob pregnant women have statistically significantly lower levels of vitamin B 6, vitamin C, vitamin E, RBC folate, higher CRP and IL-6 levels and higher ratio of oxidized to reduced glutathione compared with Lc pregnant women. Infants born to Ob mothers did not have statistically significantly higher measures of inflammation or oxidative stress. There were no differences in micronutrient concentrations between Lc and Ob infants, but folate, vitamin B 6 and zinc levels correlated strongly between mother and infant. There was no statistically significant difference in any parameter between Ob and Lc cord blood.Conclusion:Ob pregnant women have increased inflammation and oxidative stress, and lower levels of nutritional antioxidant defenses compared with Lc pregnant women. We speculate that lower antioxidant defenses combined with increased oxidative stress and inflammation may contribute to the adverse outcomes associated with pregnancy in Ob women. © 2014 Nature America, Inc. All rights reserved.

Hui L.,Mother Infant Research Institute | Hui L.,University of Sydney | Bianchi D.W.,Mother Infant Research Institute
Trends in Genetics | Year: 2013

The amount of genetic and genomic information obtainable from the human fetus during pregnancy is accelerating at an unprecedented rate. Two themes have dominated recent technological advances in prenatal diagnosis: interrogation of the fetal genome in increasingly high resolution and the development of non-invasive methods of fetal testing using cell-free DNA in maternal plasma. These two areas of advancement have now converged with several recent reports of non-invasive assessment of the entire fetal genome from maternal blood. However, technological progress is outpacing the ability of the healthcare providers and patients to incorporate these new tests into existing clinical care, and further complicates many of the economic and ethical dilemmas in prenatal diagnosis. This review summarizes recent work in this field and discusses the integration of these new technologies into the clinic and society. © 2012 Elsevier Ltd.

Neri C.,Catholic University of the Sacred Heart | Edlow A.G.,Tufts Medical Center | Edlow A.G.,Mother Infant Research Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2016

Maternal obesity has become a worldwide epidemic. Obesity and a high-fat diet have been shown to have deleterious effects on fetal programming, predisposing offspring to adverse cardiometabolic and neurodevelopmental outcomes. Although large epidemiological studies have shown an association between maternal obesity and adverse outcomes for offspring, the underlying mechanisms remain unclear. Molecular approaches have played a key role in elucidating the mechanistic underpinnings of fetal malprogramming in the setting of maternal obesity. These approaches include, among others, characterization of epigenetic modifications, microRNA expression, the gut microbiome, the transcriptome, and evaluation of specific mRNAexpression via quantitative reverse transcription polmerase chain reaction (RT-qPCR) in fetuses and offspring of obese females. This work will review the data from animal models and human fluids/cells regarding the effects of maternal obesity on fetal and offspring neurodevelopment and cardiometabolic outcomes, with a particular focus on molecular approaches. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

Edlow A.G.,Mother Infant Research Institute | Bianchi D.W.,Mother Infant Research Institute
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Current monitoring of fetal development includes fetal ultrasonography, chorionic villus sampling or amniocentesis for chromosome analysis, and maternal serum biochemical screening for analytes associated with aneuploidy and open neural tube defects. Over the last 15. years, significant advances in noninvasive prenatal diagnosis (NIPD) via cell-free fetal (cff) nucleic acids in maternal plasma have resulted in the ability to determine fetal sex, RhD genotype, and aneuploidy. Cff nucleic acids in the maternal circulation originate primarily from the placenta. This contrasts with cff nucleic acids in amniotic fluid, which derive from the fetus, and are present in significantly higher concentrations than in maternal blood. The fetal origin of cff nucleic acids in the amniotic fluid permits the acquisition of real-time information about fetal development and gene expression. This review seeks to provide a comprehensive summary of the molecular analysis of cff nucleic acids in maternal biofluids to elucidate mechanisms of fetal development, physiology, and pathology. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. © 2012 Elsevier B.V.

Zwemer L.M.,Mother Infant Research Institute | Bianchi D.W.,Mother Infant Research Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2015

Numerous recent studies have shown the power of cell-free fetal RNA, obtained from amniotic fluid supernatant, to report on the development of the living fetus in real time. Examination of these transcripts on a genome-wide basis has led to new insights into the prenatal pathophysiology of multiple genetic, developmental, and environmental diseases. Each studied condition presents a unique, characteristic fetal transcriptome, which points to specific disrupted molecular pathways. These studies have also improved our knowledge of the normal development of the human fetus, revealing gestational age-related dynamic gene expression from a variety of organs. Analysis of the fetal transcriptome in normal and abnormal development has led to novel approaches for in utero prenatal treatment. © 2015 Cold Spring Harbor Laboratory Press; All rights reserved.

Maron J.L.,Mother Infant Research Institute
Cold Spring Harbor Perspectives in Medicine | Year: 2016

The ability to noninvasively assess the physical and developmental status of a neonate is a goal of modern medicine. In recent years, technological advances have permitted the highthroughput analysis of saliva for thousands of genes, proteins, and metabolites from a single sample source. Saliva is an ideal biofluid to assess health, disease, and development in the newborn. It may be harnessed repeatedly, even in the most vulnerable patients, without risk of harm. Translating novel information about an infant’s global development and risk of disease to the neonatal bedside through the salivary transcriptome has the potential to significantly improve clinical care and outcomes in this at-risk population. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

Bianchi D.W.,Mother Infant Research Institute | Parsa S.,Mother Infant Research Institute | Bhatt S.,Mother Infant Research Institute | Halks-Miller M.,Mother Infant Research Institute | And 3 more authors.
Obstetrics and Gynecology | Year: 2015

OBJECTIVE:: To describe the clinical experience with noninvasive prenatal testing for fetal sex chromosomes using sequencing of maternal plasma cell-free DNA in a commercial laboratory. METHODS:: A noninvasive prenatal testing laboratory data set was examined for samples in which fetal sex chromosomes were reported. Available clinical outcomes were reviewed. RESULTS:: Of 18,161 samples with sex chromosome results, no sex chromosome aneuploidy was detected in 98.9% and the fetal sex was reported as XY (9,236) or XX (8,721). In 4 of 32 cases in which the fetal sex was reportedly discordant between noninvasive prenatal testing and karyotype or ultrasonogram, a potential biological reason for the discordance exists, including two cases of documented co-twin demise, one case of a maternal kidney transplant from a male donor, and one case of fetal ambiguous genitalia. In the remaining 204 samples (1.1%), one of four sex chromosome aneuploidies (monosomy X, XXX, XXY, or XYY) was detected. The frequency of false positive results for sex chromosome aneuploidies is a minimum of 0.26% and a maximum of 1.05%. All but one of the discordant sex chromosome aneuploidy results involved the X chromosome. In two putative false-positive XXX cases, maternal XXX was confirmed by karyotype. For the false-positive cases, mean maternal age was significantly higher in monosomy X (P<.001) and lower in XXX (P=.008). CONCLUSION:: Noninvasive prenatal testing results for sex chromosome aneuploidy can be confounded by maternal or fetal biological phenomena. When a discordant noninvasive prenatal testing result is encountered, resolution requires additional maternal history, detailed fetal ultrasonography, and determination of fetal and possibly maternal karyotypes. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc.

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