sendigR: an R package to leverage the value of CDISC SEND datasets for cross-study analysis.

The CDISC Standard for Exchange of Nonclinical Data (SEND) data standard has created new opportunities for collaborative development of open-source software solutions to facilitate cross-study analyses of toxicology study data. A public-private partnership between BioCelerate and the FDA/Center for Drug Evaluation and Research (CDER) was established in part to develop and publicize novel methods to facilitate cross-study analysis of SEND datasets. As part of this work in collaboration with the Pharmaceutical Users Software Exchange (PHUSE), an R package sendigR has been developed to enable users to construct a relational database from a collection of SEND datasets and then query that database to perform cross-study analyses.

Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories.

Leveraging the Value of CDISC SEND Data Sets for Cross-Study Analysis: Incidence of Microscopic Findings in Control Animals.

Implementation of the Clinical Data Interchange Standards Consortium (CDISC)'s Standard for Exchange of Nonclinical Data (SEND) by the United States Food and Drug Administration Center for Drug Evaluation and Research (US FDA CDER) has created large quantities of SEND data sets and a tremendous opportunity to apply large-scale data analytic approaches. To fully realize this opportunity, differences in SEND implementation that impair the ability to conduct cross-study analysis must be addressed. In this manuscript, a prototypical question regarding historical control data (see Table of Contents graphic) was used to identify areas for SEND harmonization and to develop algorithmic strategies for nonclinical cross-study analysis within a variety of databases.

SEND harmonization & cross-study analysis: A proposal to better harvest the value from SEND data.

The Standard for Exchange of Nonclinical Data (SEND) identifies an approach for representing nonclinical data in a structured format which has been widely adopted by the pharmaceutical industry as it is required for data submission to the United States Food & Drug Administration (US FDA). The SEND Implementation Guide (SENDIG) allows for considerable flexibility in how data is represented; interpretation of these guidelines has led to significant variability in the approach to SEND dataset creation. The purposes of this manuscript are to identify common variability in certain SEND domains and to describe how variability can be managed to enable valuable cross-study analysis use cases.

Combining recombinant ribonuclease U2 and protein phosphatase for RNA modification mapping by liquid chromatography-mass spectrometry.

Ribonuclease (RNase) mapping of modified nucleosides onto RNA sequences is limited by RNase availability. A codon-optimized gene for RNase U2, a purine selective RNase with preference for adenosine, has been designed for overexpression using Escherichia coli as the host. Optimal expression conditions were identified enabling generation of milligram-scale quantities of active RNase U2.

"I'm a storyteller!": Exploring the benefits of TimeSlips creative expression program at a nursing home.

Background: TimeSlips creative storytelling program is beneficial for persons with dementia and caregivers, but no studies have qualitatively explored participant experience.

Methods: Ten residents in a skilled nursing care unit participated in 2-hour-long TimeSlips sessions per week, for 6 weeks. Semistructured interviews of participants and staff members were conducted to elicit perceptions of TimeSlips.

Impact of TimeSlips creative expression program on behavioral symptoms and psychotropic medication use in persons with dementia in long-term care: a cluster-randomized pilot study.

Objectives: To evaluate whether involvement in TimeSlips, a creative storytelling program, reduced mood and behavioral symptoms as well as psychotropic medication use in persons with dementia.

Methods: A cluster-randomized pilot study compared two discrete dementia care units in one nursing home. The control cohort (N = 10) received standard-of-care activity programming, and the intervention cohort (N = 10) received standard-of-care plus two one-hour TimeSlips sessions per week for six weeks.

FDA Engages Collaborators to Address Nonclinical Data Challenges.

FDA and PhUSE cohosted a Computational Science Symposium (CSS) in 2012 that brought stakeholders from the pharmaceutical industry and government to work collaboratively to solve common needs and challenges. A nonclinical informatics workgroup was formed, dedicated to improving nonclinical assessments and regulatory science by identifying, collecting, and prioritizing key needs and challenges in the field and then establishing an innovative framework for addressing them in a collaborative manner. This paper discusses the process and outcomes of the nonclinical informatics workgroup during the CSS and describes an approach which crossed organizational barriers to optimize computational science for nonclinical assessment.

Evaluation of the energy cost of playing a dance simulation video game in overweight and non-overweight children and adolescents.

The purpose of this study was to determine if there were any differences in the submaximal energy cost of movement between overweight (OW) and non-overweight (NO) children while playing a dance simulation video game, Dance Dance Revolution (DDR) and to determine if the cardiorespiratory measures obtained while playing the game met the American College of Sports Medicine (ACSM) recommendations for developing and maintaining cardiorespiratory fitness. Twenty-two children and adolescents (10 OW vs. 12 NO) participated in the study.

Localization of trapping of 6-[(18)F]fluoro-L-m-tyrosine, an aromatic L-amino acid decarboxylase tracer for PET.

The purpose of this study was to address four major questions regarding 6-FMT, a noncatecholic PET tracer for AAAD: 1) Where is the specific uptake of 6-FMT? 2) Why does it accumulate where and to the degree that it does? 3) How does its uptake differ from that of fluoroDOPA globally? and 4) Does its regional uptake differ significantly from that of fluoroDOPA? High-resolution PET scans were obtained in three rhesus monkeys using 6-FMT and in two of them using fluoroDOPA. Anatomic distribution was analyzed visually and quantitative uptake of 6-FMT was compared with published regional decarboxylase activity and monoamine neurotransmitter concentrations. In addition to high uptake in the dopamine-rich striatal nuclei, there was specific uptake of 6-FMT in brain regions which have little dopaminergic innervation but which have other amines in significant concentration.

Colon cancer in aged captive rhesus monkeys (Macaca mulatta).

The age-related incidence of malignant neoplasia was surveyed from a total of 301 necropsy cases of rhesus monkeys ranging in age from 13-37 years performed in the Pathology Service Unit of the Wisconsin Regional Primate Research Center during the past 15 years. All our aged monkeys lived in indoor cages and were fed with monkey chow and supplemental fruits during the past decades. In this survey, we found a total of 51 malignant neoplasms, and among them 25 cases were colon cancer.

Esophageal candidiasis as a complication of inhaled corticosteroids.

Background: Oropharyngeal candidiasis is a well-described side effect of inhaled corticosteroids. Nevertheless, few cases of esophageal candidiasis have been reported.

Objective: To present a patient with esophageal candidiasis associated with inhaled corticosteroids.

Dichloroacetic acid treatment increases hepatic CYP2E1 in male and female rats.

Previously, we showed that the pretreatment of dichloroacetic acid (DCA) increased CHCl3-induced hepatotoxicity in vivo and CHCl3 metabolism in vitro in both male and female rats. The effects of DCA on hepatic cytochrome P450-dependent monooxygenases were studied in this experiment. Male and female Sprague-Dawley rats were treated with DCA (each 2.

Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques.

In the present study, we report our extended data on the incidence of two types of cerebral amyloidosis (plaques and plaques associated with angiopathy) and visceral amyloidosis in late adult and aged captive rhesus monkeys (Macaca mulatta). In a total of 81 brains from animals ranging from 16 to 39 years old, beta-amyloid plaques were found in 38, 10 of which were associated with amyloid angiopathy. Brains from eight adults, 16 to 19 years, had no lesions.

Characterization of 5' end of human thromboxane receptor gene. Organizational analysis and mapping of protein kinase C--responsive elements regulating expression in platelets.

Platelet thromboxane receptors are acutely and reversibly upregulated after acute myocardial infarction. To determine if platelet thromboxane receptors are under transcriptional control, we isolated and characterized human genomic DNA clones containing the 5' flanking region of the thromboxane receptor gene. The exon-intron structure of the 5' portion of the thromboxane receptor gene was determined initially by comparing the nucleotide sequence of the 5' flanking genomic clone with that of a novel human uterine thromboxane receptor cDNA that extended the mRNA 141 bp further upstream than the previously identified human placental cDNA.

Induction of CYP1A1 gene expression in H4-II-E rat hepatoma cells by benzo[e]pyrene.

In the rat, expression of the CYP1A1 gene is closely associated with arylhydrocarbon hydroxylase (AHH) enzyme activity. AHH is an inducile enzyme activity known to play an important role in the bioactivation of polycyclic aromatic hydrocarbons (PAHs) to mutagenic and carcinogenic metabolites. PAH-induced expression of the CYP1A1 gene appears to be regulated by several trans-acting factors, including the Ah receptor and the 4S PAH-binding protein.

Presence of the 4 S polycyclic hydrocarbon-binding protein in H4-II-E cells.

The 4 S polycyclic aromatic hydrocarbon (PAH)-binding protein had been implicated in regulating the expression of rat cytochrome P450IA1 which is most closely associated with aryl hydrocarbon hydroxylase (AHH). We have now investigated the presence of both the 4 S PAH-binding protein and the 8 S Ah receptor in rat hepatoma H4-II-E cells as well as the induction of P450IA1 upon their exposure to PAH's such as benzo[a]pyrene (BP) and 3-methylcholanthrene (3MC), and halogenated dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDBF). Sucrose density gradient analyses and hydroxylapatite assays indicate that, in addition to the 8 S protein, the 4 S PAH binding protein is present in these cells.

Evaluation of the 4S polycyclic aromatic hydrocarbon binding protein in the Harlan Sprague-Dawley rat.

The polycyclic aromatic hydrocarbon (PAH)-induced expression of the rat Cyp1A1 gene is a complex process which appears to be regulated by several trans-acting factors including the 8S (Ah receptor) and 4S PAH binding proteins. This gene is closely associated with aryl hydrocarbon hydroxylase enzyme activity (AHH), which is known to bioactivate PAHs. The current study was undertaken to examine the hepatic 4S PAH binding protein in male Harlan Sprague-Dawley (HSD) rats using sucrose gradient analysis of 100,000 g supernatant solutions incubated with 10 nM [3H]benzo[a]pyrene (B[a]P) and a 200-fold excess of competitive ligands.

Binding characteristics of 4S PAH-binding protein and Ah receptor from rats and mice.

Cytochrome P-450IA1 (Cyto-P450IA1) is the isozyme most closely associated with aryl hydrocarbon hydroxylase (AHH). At least two distinct high-affinity binding proteins may regulate its expression, the 4S protein that primarily binds polycyclic aromatic hydrocarbons (PAHs), and the 8S Ah receptor that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and like congeners. The present study was conducted to investigate ligand binding characteristics of the 4S and 8S binding proteins before and after separation from liver cytosol in the presence and absence of sodium molybdate.

Binding of the 97 kDa glucocorticoid receptor to the 5' upstream flanking region of the mouse c-Ha-ras oncogene.

Glucocorticoids regulate transcription of specific genes through the interaction of glucocorticoid hormone receptor complexes with DNA binding sites called glucocorticoid response elements (GREs). The GRE consensus sequence has been defined to be the imperfect palindromic sequence 5'-GGTACANNNTGTTCT-3', the most highly conserved portion being the 5'-TGTTCT-3' hexamer. We have identified 5 potential GREs in the 5' upstream noncoding region of the mouse c-Ha-ras oncogene, two with the same hexanucleotide sequence and three with a similar sequence.

Establishment of hamster pancreatic ductal carcinoma cell line (PC-1) producing blood group-related antigens.

A pancreatic cancer cell line, PC-1, was established from a pancreatic ductal carcinoma induced in a hamster by N-nitrosobis(2-oxopropyl)amine (BOP). The cells grew in a monolayer with a doubling time of 38 h, and floated or piled up to form a duct-like structure. Chromosome counts ranged from 42 to 89.

Glucocorticoid regulation of the rat cytochrome P450c (P450IA1) gene: receptor binding within intron I.

The actions of polycyclic aromatic hydrocarbons and glucocorticoids to regulate the expression of cytochrome P450c were investigated using cultured fetal rat hepatocytes. Cytochrome P450c mRNA content, determined by Northern blot analysis, was induced in cells treated with 1,2-benzanthracene from levels undetectable in untreated cells. When dexamethasone was included in the culture medium together with 1,2-benzanthracene there was a further 2-fold increase in the induction of cytochrome P450c mRNA.

The 4S binding protein acts as a trans-regulator of the polycyclic hydrocarbon-inducible cytochrome P450.

A model has been proposed for the induction of cytochrome P450c in liver by polycyclic hydrocarbons such as benzo(a)pyrene (BaP) and 3-methylcholanthrene (3MC). The polycyclic hydrocarbon interacts in specific, saturable, and high-affinity fashion with a rat liver cytosolic 4s binding protein. The latter enters the nucleus, complexes to 5' upstream regions of the cytochrome P450c gene, and stimulates the transcription.

Aging and immunity in nonhuman primates: I. Effects of age and gender on cellular immune function in rhesus monkeys (Macaca mulatta).

Immunity declines with advancing age. Lymphocyte proliferation, natural killer cell activity, and antibody response to tetanus toxoid vaccination were evaluated in cohorts of rhesus monkeys (Macaca mulatta) aged 2-36 years in order to characterize senescent changes in immune function. The results were analyzed in accordance with host age.

Interaction of the 4 S polycyclic aromatic hydrocarbon-binding protein with the cytochrome P-450c gene.

The induction of cytochrome P-450c, the isozyme most closely associated with aryl hydrocarbon hydroxylase activity in the rat, is mediated through a cytosolic polycyclic aromatic hydrocarbon (PAH)-binding protein(s). We have reported on the purification and characterization of a 4 S protein that interacts in a specific and saturable manner with [3H]benzo[a]pyrene and other PAHs. (W.