An Opportunity to Fill a Gap for Newborn Screening of Neurodevelopmental Disorders.

Screening newborns using genome sequencing is being explored due to its potential to expand the list of conditions that can be screened. Previously, we proposed the need for large-scale pilot studies to assess the feasibility of screening highly penetrant genetic neurodevelopmental disorders. Here, we discuss the initial experience from the GUARDIAN study and the systemic gaps in clinical services that were identified in the early stages of the pilot study.

NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders.

Rapid advances in the screening, diagnosis, and treatment of genetic disorders have increased the number of conditions that can be detected through universal newborn screening (NBS). However, the addition of conditions to the Recommended Uniform Screening Panel (RUSP) and the implementation of nationwide screening has been a slow process taking several years to accomplish for individual conditions. Here, we describe web-based tools and resources developed and implemented by the newborn screening translational research network (NBSTRN) to advance newborn screening research and support NBS stakeholders worldwide.

Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early.

Analytical performance of Envisia: a genomic classifier for usual interstitial pneumonia.

Background: Clinical guidelines specify that diagnosis of interstitial pulmonary fibrosis (IPF) requires identification of usual interstitial pneumonia (UIP) pattern. While UIP can be identified by high resolution CT of the chest, the results are often inconclusive, making surgical lung biopsy necessary to reach a definitive diagnosis (Raghu et al., Am J Respir Crit Care Med 183(6):788-824, 2011).

Analytical Performance of a Gene Expression Classifier for Medullary Thyroid Carcinoma.

Background: The aim of this study was to demonstrate the analytical validity of an RNA classifier for medullary thyroid carcinoma (MTC).

Methods: Fresh-frozen tissue specimens were obtained from commercial sources, and MTC diagnoses were confirmed by histopathology review. De-identified patient fine-needle aspiration biopsies (FNABs) and whole blood from normal donors were obtained.

Analytical performance of a bronchial genomic classifier.

Background: The current standard practice of lung lesion diagnosis often leads to inconclusive results, requiring additional diagnostic follow up procedures that are invasive and often unnecessary due to the high benign rate in such lesions (Chest 143:e78S-e92, 2013). The Percepta bronchial genomic classifier was developed and clinically validated to provide more accurate classification of lung nodules and lesions that are inconclusive by bronchoscopy, using bronchial brushing specimens (N Engl J Med 373:243-51, 2015, BMC Med Genomics 8:18, 2015). The analytical performance of the Percepta test is reported here.

Machine learning from concept to clinic: reliable detection of BRAF V600E DNA mutations in thyroid nodules using high-dimensional RNA expression data.

The promise of personalized medicine will require rigorously validated molecular diagnostics developed on minimally invasive, clinically relevant samples. Measurement of DNA mutations is increasingly common in clinical settings but only higher-prevalence mutations are cost-effective. Patients with rare variants are at best ignored or, at worst, misdiagnosed.

Exon-level expression profiling: a comprehensive transcriptome analysis of oral fluids.

Background: The application of global gene expression profiling to saliva samples is hampered by the presence of partially fragmented and degraded RNAs that are difficult to amplify and detect with the prevailing technologies. Moreover, the often limited volume of saliva samples is a challenge to quantitative PCR (qPCR) validation of multiple candidates. The aim of this study was to provide proof-of-concept data on the combination of a universal mRNA-amplification method with exon arrays for candidate selection and a multiplex preamplification method for easy validation.

Involvement of JNK/p73/NOXA in vitamin E analog-induced apoptosis of human breast cancer cells.

Microarray analyses of human MDA-MB-435 breast cancer cells treated with vitamin E analog 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy acetic acid (alpha-TEA) showed over 400 genes to be modulated. Thirty-four genes deemed of interest based on potential involvement in anticancer activities of alpha-TEA fell into six categories: apoptosis related, signal transduction, cell cycle related, cell adhesion and motility, transcriptional regulators, and membrane traffic related. The gene (PMAIP1) for NOXA was studied further.

Genetic reconstruction of a functional transcriptional regulatory network.

Although global analyses of transcription factor binding provide one view of potential transcriptional regulatory networks, regulation also occurs at levels distinct from transcription factor binding. Here, we use a genetic approach to identify targets of transcription factors in yeast and reconstruct a functional regulatory network. First, we profiled transcriptional responses in S.

The heme activator protein Hap1 represses transcription by a heme-independent mechanism in Saccharomyces cerevisiae.

The yeast heme activator protein Hap1 binds to DNA and activates transcription of genes encoding functions required for respiration and for controlling oxidative damage, in response to heme. Hap1 contains a DNA-binding domain with a C6 zinc cluster motif, a coiled-coil dimerization element, typical of the members of the yeast Gal4 family, and an acidic activation domain. The regulation of Hap1 transcription-activating activity is controlled by two classes of Hap1 elements, repression modules (RPM1-3) and heme-responsive motifs (HRM1-7).

Genome-wide analysis of the biology of stress responses through heat shock transcription factor.

Heat shock transcription factor (HSF) and the promoter heat shock element (HSE) are among the most highly conserved transcriptional regulatory elements in nature. HSF mediates the transcriptional response of eukaryotic cells to heat, infection and inflammation, pharmacological agents, and other stresses. While HSF is essential for cell viability in Saccharomyces cerevisiae, oogenesis and early development in Drosophila melanogaster, extended life span in Caenorhabditis elegans, and extraembryonic development and stress resistance in mammals, little is known about its full range of biological target genes.