Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model.

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model.

Human epidermal growth factor receptor 2 (Her2) testing for uterine serous carcinoma: Report of scenarios of unusual overexpression.

The human epidermal growth factor receptor 2 (Her2) is tested in many human cancers, including breast, bladder, pancreatic, ovarian and stomach. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) have issued Clinical Practice Guidelines for reporting Her2 results for breast carcinomas (Wolf et al., 2018).

Ovotesticular Disorder of Sex Development (Ovotestis) in Simpson-Golabi-Behmel Syndrome: Expansion of the Clinical Spectrum.

Simpson-Golabi-Behmel syndrome type I (SGBS, OMIM312870), caused by defects of the GPC3 and GPC4 genes on chromosome Xq26, is an X-linked recessive macrosomia/multiple congenital anomaly disorder characterized by somatic overgrowth, coarse facial features, variable congenital anomalies, increased tumor risk, and mild-to-moderate neurodevelopmental anomalies. We report the postmortem findings in 3 second-trimester male siblings with SGBS who displayed ambiguous genitalia (in all 3) and gonadal dysgenesis (ovotestis) (in 1), thus expanding the SGBS spectrum to include these disorders of sex development.

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.

Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.

Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers.

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell).

Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit.

Protein phosphatase 6 (PP6) is a ubiquitous Ser/Thr phosphatase involved in an array of cellular processes. To assess the potential of PP6 as a therapeutic target in liver disorders, we attenuated expression of the PP6 catalytic subunit in HepG2 cells using lentiviral-transduced shRNA. Two PP6 knock-down (PP6KD) cell lines (90% reduction of PP6-C protein content) were studied in depth.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

Objective: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS.

Methods: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized.

Monochorionic twins discordant for mosaic trisomy 14.

Monochorionic-diamniotic twins are usually monozygotic twins and known to be associated with adverse obstetric and perinatal outcomes. Cases of discordant karyotype of monozygotic twins are rare and most involves sex chromosomes. We present the first case of monochorionic twins with discordant karyotype manifested as mosaic trisomy 14 in one twin (B) and a normal karyotype in the other (A).

An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma.

We report on a pedigree with a pair of brothers each with minor anomalies, developmental delay, and autistic-symptoms who share an unbalanced translocation (not detectable by karyotype). The unbalanced translocation involves a 7.1 Mb loss of the terminal portion of 10q, and a 4.

Proof of concept study to assess fetal gene expression in amniotic fluid by nanoarray PCR.

Microarray analysis of cell-free RNA in amniotic fluid (AF) supernatant has revealed differential fetal gene expression as a function of gestational age and karyotype. Once informative genes are identified, research moves to a more focused platform such as quantitative reverse transcriptase-PCR. Standardized NanoArray PCR (SNAP) is a recently developed gene profiling technology that enables the measurement of transcripts from samples containing reduced quantities or degraded nucleic acids.

Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18.

Trisomy 18 is a common human aneuploidy that is associated with significant perinatal mortality. Unlike the well-characterized "critical region" in trisomy 21 (21q22), there is no corresponding region on chromosome 18 associated with its pathogenesis. The high morbidity and mortality of affected individuals has limited extensive investigations.

Accumulation of neoplastic traits prior to spontaneous in vitro transformation of rat cholangiocytes determines susceptibility to activated ErbB-2/Neu.

Cholangiocarcinoma, a severe form of biliary cancer, has a high mortality rate resulting partially from the advanced stage of disease at earliest diagnosis. A better understanding of the progressive molecular and cellular changes occurring during spontaneous cholangiocarcinogenesis is needed to identify potential biomarkers for diagnosis/prognosis or targets for novel therapeutics. Here, we show that with continued passage (p) in vitro, rat bile duct epithelial cells (BDEC) accumulated neoplastic characteristics that by mid-passage (p31-85) included alterations in morphology, increased growth rate, growth factor independence, decreased cell adhesion, loss of cholangiocyte markers expressed at low passage (p<30), and onset of aneuploidy.

Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses.

To characterize the differences between second trimester Down syndrome (DS) and euploid fetuses, we used Affymetrix microarrays to compare gene expression in uncultured amniotic fluid supernatant samples. Functional pathway analysis highlighted the importance of oxidative stress, ion transport, and G protein signaling in the DS fetuses. Further evidence supporting these results was derived by correlating the observed gene expression patterns to those of small molecule drugs via the Connectivity Map.

Utility of fetal karyotype in the evaluation of phenotypically abnormal stillbirths.

The objectives of this study are to test the hypothesis that stillbirths without aneuploidy-associated phenotypes have a low incidence of karyotypic abnormalities, similar among those with and without other anatomic defects. We employed a uniform postmortem protocol to examine fetuses and placentas in 962 consecutive stillbirths measuring > or =20 weeks in clinically determined gestational age submitted to the Women and Infants Hospital Division of Perinatal Pathology from 1990 through 2005. Classification of anatomic (macroscopic) abnormalities was based on a priori criteria.

Fas-ligand-induced apoptosis of respiratory epithelial cells causes disruption of postcanalicular alveolar development.

Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasia- associated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs.

Effects of chemotherapy during pregnancy on the placenta.

Whereas the effects of chemotherapy during pregnancy for mother and fetus are well described, its effects on the placenta remain largely undetermined. We performed a retrospective clinicopathologic analysis of the placenta following chemotherapy. Charts were reviewed for type of malignancy, type and timing of chemotherapy, and fetal and pregnancy outcome.

Activin subunit and receptor expression in normal and cleft human fetal palate tissues.

Craniofacial malformations, such as cleft palate, present serious complications in the newborn and are often of unknown etiology. Activin BA subunit deletion leads to cleft palate in mice, but the expression of this protein in the human palate has not been explored. Our goal was to determine the spatial and temporal expression of inhibin/activin subunits; the binding protein, follistatin; and activin receptors in the human fetal palate.

Array-CGH analysis of cell-free fetal DNA in 10 mL of amniotic fluid supernatant.

Background: Previously, we showed that analysis of amniotic fluid (AF) supernatant cell-free fetal (cff) DNA using DNA microarrays (array-CGH) allows for detection of whole chromosome differences between test and reference DNA. Subsequent technical advances have increased both the yield and quality of extracted cffDNA. Here we determined whether array-CGH using smaller volumes of both fresh and frozen AF cffDNA could identify fetal aneuploidy.

Cell-free fetal DNA in amniotic fluid: unique fragmentation signatures in euploid and aneuploid fetuses.

Background: Circulating cell-free fetal deoxyribonucleic acids (cffDNA) are novel biomarkers with many clinical applications. Amniotic fluid (AF) is a rich source of cffDNA. We investigated the biophysical characteristics of cffDNA in AF, hypothesizing that they would differ from cffDNA in maternal plasma.

Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.

Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study.

Methods And Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.

Periventricular nodular heterotopia and Williams syndrome.

We report here on the first case of a child with bilateral periventricular nodular heterotopia (PNH) and Williams syndrome. Fluorescent in situ hybridization (FISH) analyses demonstrated a deletion of the elastin gene in the Williams syndrome critical region (WSCR). Further mapping by loss of heterozygosity analysis both by microsatellite marker and SNP profiling demonstrated a 1.

Second-trimester maternal serum markers in twin pregnancy with complete mole: report of 2 cases.

We present second-trimester serum marker levels in cases of twin pregnancy with complete hydatidiform mole and a coexistent fetus (CHMCF). Second-trimester inhibin A (InhA) levels have not been previously reported in such cases. Second-trimester maternal serum screening, alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and InhA measurements combined with maternal age to estimate a patient's risk of Down syndrome during pregnancy was performed as a routine prenatal test in 2 cases of CHMCF.

Global gene expression analysis of the living human fetus using cell-free messenger RNA in amniotic fluid.

Context: No molecular biological tests are available to monitor the ongoing development of human fetuses in vivo.

Objective: To determine whether cell-free fetal messenger RNA (mRNA) in amniotic fluid can be detected using oligonucleotide microarrays to study large-scale gene expression in living human fetuses, with analysis of sex, gestational age, and fetal pathology as variables.

Design, Setting, And Patients: Four samples of cell-free amniotic fluid were analyzed from pregnant women between 20 and 32 weeks' gestation and undergoing amnioreduction for polyhydramnios associated with twin-twin transfusion syndrome or hydrops fetalis (cases).