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author:("holtzman, Ted")
1.  Metabolomic Profiling of Urine: Response to a Randomized, Controlled Feeding Study of Select Fruits and Vegetables, and Application to an Observational Study 1,2 
The British journal of nutrition  2013;110(10):10.1017/S000711451300127X.
Metabolomic profiles were used to characterize the effects of consuming a high-phytochemical diet compared to a diet devoid of fruits and vegetables in a randomized trial and cross-sectional study. In the trial, 8 h fasting urine from healthy men (n=5) and women (n=5) was collected after a 2-week randomized, controlled trial of 2 diet periods: a diet rich in cruciferous vegetables, citrus and soy (F&V), and a fruit- and vegetable-free (basal) diet. Among the ions found to differentiate the diets, 176 were putatively annotated with compound identifications, with 46 supported by MS/MS fragment evidence. Metabolites more abundant in the F&V diet included markers of dietary intervention (e.g., crucifers, citrus and soy), fatty acids and niacin metabolites. Ions more abundant in the basal diet included riboflavin, several acylcarnitines, and amino acid metabolites. In the cross-sectional study, we compared participants based on tertiles of crucifers, citrus and soy from 3 d food records (3DFR; n=36) and food frequency questionnaires (FFQ; n=57); intake was separately divided into tertiles of total fruit and vegetable intake for FFQ. As a group, ions individually differential between the experimental diets differentiated the observational study participants. However, only 4 ions were significant individually, differentiating the third vs. first tertile of crucifer, citrus and soy intake based on 3FDR. One of these was putatively annotated: proline betaine, a marker of citrus consumption. There were no ions significantly distinguishing tertiles by FFQ. Metabolomics assessment of controlled dietary interventions provides a more accurate and stronger characterization of diet than observational data.
PMCID: PMC3818452  PMID: 23657156
2.  Proteome and Transcriptome Profiles of a Her2/Neu-driven Mouse Model of Breast Cancer 
Proteomics. Clinical applications  2011;5(3-4):179-188.
We generated extensive transcriptional and proteomic profiles from a Her2-driven mouse model of breast cancer that closely recapitulates human breast cancer. This report makes these data publicly available in raw and processed forms, as a resource to the community. Importantly, we previously made biospecimens from this same mouse model freely available through a sample repository, so researchers can obtain samples to test biological hypotheses without the need of breeding animals and collecting biospecimens.
Experimental design
Twelve datasets are available, encompassing 841 LC-MS/MS experiments (plasma and tissues) and 255 microarray analyses of multiple tissues (thymus, spleen, liver, blood cells, and breast). Cases and controls were rigorously paired to avoid bias.
In total, 18,880 unique peptides were identified (PeptideProphet peptide error rate ≤1%), with 3884 and 1659 non-redundant protein groups identified in plasma and tissue datasets, respectively. Sixty-one of these protein groups overlapped between cancer plasma and cancer tissue.
Conclusions and clinical relevance
These data are of use for advancing our understanding of cancer biology, for software and quality control tool development, investigations of analytical variation in MS/MS data, and selection of proteotypic peptides for MRM-MS. The availability of these datasets will contribute positively to clinical proteomics.
PMCID: PMC3069718  PMID: 21448875
Breast cancer; Her2; mouse; proteome; transcriptome
3.  MRMer, an Interactive Open Source and Cross-platform System for Data Extraction and Visualization of Multiple Reaction Monitoring Experiments*S⃞ 
Multiple reaction monitoring (MRM) mass spectrometry identifies and quantifies specific peptides in a complex mixture with very high sensitivity and speed and thus has promise for the high throughput screening of clinical samples for candidate biomarkers. We have developed an interactive software platform, called MRMer, for managing highly complex MRM-MS experiments, including quantitative analyses using heavy/light isotopic peptide pairs. MRMer parses and extracts information from MS files encoded in the platform-independent mzXML data format. It extracts and infers precursor-product ion transition pairings, computes integrated ion intensities, and permits rapid visual curation for analyses exceeding 1000 precursor-product pairs. Results can be easily output for quantitative comparison of consecutive runs. Additionally MRMer incorporates features that permit the quantitative analysis experiments including heavy and light isotopic peptide pairs. MRMer is open source and provided under the Apache 2.0 license.
PMCID: PMC2577205  PMID: 18641041
4.  Genomewide scan for real-word reading subphenotypes of dyslexia: Novel chromosome 13 locus and genetic complexity 
Dyslexia is a common learning disability exhibited as a delay in acquiring reading skills despite adequate intelligence and instruction. Reading single real words (real-word reading, RWR) is especially impaired in many dyslexics. We performed a genome scan, using variance-components (VC) linkage analysis and Bayesian Markov chain Monte Carlo (MCMC) joint segregation and linkage analysis, for three quantitative measures of RWR in 108 multigenerational families, with followup of the strongest signals with parametric LOD score analyses. We used single-word reading efficiency (SWE) to assess speed and accuracy of RWR, and word identification (WID) to assess accuracy alone. Adjusting SWE for WID provided a third measure of RWR efficiency.
All three methods of analysis identified a strong linkage signal for SWE on chromosome 13q. Based on multipoint analysis with 13 markers we obtained a MCMC intensity ratio of 53.2 (chromosome-wide p < 0.004), a VC LOD score of 2.29, and a parametric LOD score of 2.94, based on a quantitative-trait model from MCMC segregation analysis. A weaker signal for SWE on chromosome 2q occurred in the same location as a significant linkage peak seen previously in a scan for phonological decoding. MCMC oligogenic segregation analysis identified three models of transmission for WID, which could be assigned to two distinct linkage peaks on chromosomes 12 and 15. Taken together, these results indicate a locus for efficiency and accuracy of RWR on chromosome 13, and a complex model for inheritance of RWR accuracy with loci on chromosomes 12 and 15.
PMCID: PMC2556979  PMID: 16331673
reading disability; linkage analysis; complex disorder; chromosome 13
5.  Identification and functional analysis of ‘hypothetical’ genes expressed in Haemophilus influenzae 
Nucleic Acids Research  2004;32(8):2353-2361.
The progress in genome sequencing has led to a rapid accumulation in GenBank submissions of uncharacterized ‘hypothetical’ genes. These genes, which have not been experimentally characterized and whose functions cannot be deduced from simple sequence comparisons alone, now comprise a significant fraction of the public databases. Expression analyses of Haemophilus influenzae cells using a combination of transcriptomic and proteomic approaches resulted in confident identification of 54 ‘hypothetical’ genes that were expressed in cells under normal growth conditions. In an attempt to understand the functions of these proteins, we used a variety of publicly available analysis tools. Close homologs in other species were detected for each of the 54 ‘hypothetical’ genes. For 16 of them, exact functional assignments could be found in one or more public databases. Additionally, we were able to suggest general functional characterization for 27 more genes (comprising ∼80% total). Findings from this analysis include the identification of a pyruvate-formate lyase-like operon, likely to be expressed not only in H.influenzae but also in several other bacteria. Further, we also observed three genes that are likely to participate in the transport and/or metabolism of sialic acid, an important component of the H.influenzae lipo-oligosaccharide. Accurate functional annotation of uncharacterized genes calls for an integrative approach, combining expression studies with extensive computational analysis and curation, followed by eventual experimental verification of the computational predictions.
PMCID: PMC419445  PMID: 15121896
6.  Gene Expression Profiling of the Cellular Transcriptional Network Regulated by Alpha/Beta Interferon and Its Partial Attenuation by the Hepatitis C Virus Nonstructural 5A Protein 
Journal of Virology  2003;77(11):6367-6375.
Alpha/beta interferons (IFN-α/β) induce potent antiviral and antiproliferative responses and are used to treat a wide range of human diseases, including chronic hepatitis C virus (HCV) infection. However, for reasons that remain poorly understood, many HCV isolates are resistant to IFN therapy. To better understand the nature of the cellular IFN response, we examined the effects of IFN treatment on global gene expression by using several types of human cells, including HeLa cells, liver cell lines, and primary fetal hepatocytes. In response to IFN, 50 of the approximately 4,600 genes examined were consistently induced in each of these cell types and another 60 were induced in a cell type-specific manner. A search for IFN-stimulated response elements (ISREs) in genomic DNA located upstream of IFN-stimulated genes revealed both previously identified and novel putative ISREs. To determine whether HCV can alter IFN-regulated gene expression, we performed microarray analyses on IFN-treated HeLa cells expressing the HCV nonstructural 5A (NS5A) protein and on IFN-treated Huh7 cells containing an HCV subgenomic replicon. NS5A partially blocked the IFN-mediated induction of 14 IFN-stimulated genes, an effect that may play a role in HCV resistance to IFN. This block may occur through repression of ISRE-mediated transcription, since NS5A also inhibited the IFN-mediated induction of a reporter gene driven from an ISRE-containing promoter. In contrast, the HCV replicon had very little effect on IFN-regulated gene expression. These differences highlight the importance of comparing results from multiple model systems when investigating complex phenomena such as the cellular response to IFN and viral mechanisms of IFN resistance.
PMCID: PMC155033  PMID: 12743294
7.  A Computer Terminal Program to Evaluate Cardiovascular Functional Limits and Estimate Coronary Event Risks 
Western Journal of Medicine  1981;135(4):342-350.
A system of computer terminals was set up in a group of office practices, industrial medical departments and hospitals and connected to a central computer. This service provides a means of analyzing treadmill exercise results, which are displayed graphically on the computer printout. The system also provides estimates of probabilities of primary or secondary coronary heart disease events developing based on the exercise responses.
PMCID: PMC1273203  PMID: 7342465

Results 1-7 (7)