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In Print: Sep 8, 2009

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Microarray-related papers of note published in August 2009

Journal: Bioinformatics. 2009 Aug 6. [Epub ahead of print]

Title: R/Bioconductor software for Illumina's Infinium whole-genome genotyping BeadChips.

Authors: M Ritchie; B Carvalho; K Hetrick; S Tavaré; R Irizarry

The authors of this paper argue that there is a shortage of open source software to process the raw intensities from Illumina BeadChips into genotype calls. To tackle this problem, they developed the R/Bioconductor package crlmm for analyzing BeadChip data. According to the authors, after careful preprocessing, the software applies the CRLMM algorithm to produce genotype calls, confidence scores, and other quality metrics at both the SNP- and sample-level. They also provide access to the raw summary-level intensity data, allowing users to develop their own methods for genotype calling or copy number analysis.


Journal: BMC Genomics. 2009 Aug 5;10:357.

Title: Comparative genomics in chicken and Pekin duck using FISH mapping and microarray analysis.

Authors: B Skinner; L Robertson; H Tempest; E Langley; D Ioannou; K Fowler; R Crooijmans; A Hall; D Griffin; M Völker

The authors note that the availability of the chicken genome sequence as well as chicken probes for fluorescent in situ hybridization and microarray resources facilitate comparative genomic studies between chicken and other bird species. In a previous study, the same authors provided a comprehensive cytogenetic map for turkey and the first analysis of copy number variants in birds. In this paper, they extend this approach to the Pekin duck. Specifically, they provide a detailed molecular cytogenetic map of the duck genome through FISH assignment of 155 chicken clones. They also identified one inter- and six intrachromosomal rearrangements between chicken and duck macrochromosomes and demonstrated conserved synteny among all microchromosomes analyzed. Array comparative genomic hybridization revealed 32 CNVs, of which 5 overlap previously designated hotspot regions between chicken and turkey. The authors suggest their results show extensive conservation of avian genomes across 90 million years of evolution in both macro- and microchromosomes.


Journal: BMC Microbiology. 2009 Aug 10;9(1):161. [Epub ahead of print]

Title: Rapid identification of bacterial pathogens using a PCR- and microarray-based assay.

Authors: A Jarvinen; S Laakso; P Piiparinen; A Aittakorpi; M Lindfors; L Huopaniemi; H Piiparinen; M Maki

The authors have developed a method based on a modified broad-range PCR and an oligonucleotide microarray for the simultaneous detection and identification of 12 bacterial pathogens at the species level. The feasibility of the assay in routine diagnostic testing was evaluated using 146 blood culture positive and 40 blood culture negative samples. According to the authors, after comparing their results with those of a conventional culture-based method, they found their assay has a sensitivity of 96 percent and specificity of 98 percent. Only one cross-reaction was observed upon investigating 102 culture isolates from 70 untargeted bacteria, they reported. Total assay time was three hours, including the time required for the DNA extraction, PCR, and microarray steps in sequence.


Journal: BMC Neuroscience. 2009 Aug 7;10:95.

Title: Gene expression changes following extinction testing in a heroin behavioral incubation model.

Authors: K Kuntz-Melcavage; R Brucklacher; P Grigson; W Freeman; K Vrana

In this study, genome-wide analysis of gene expression was conducted following an extinction session in rats that expressed behavioral incubation of heroin-seeking and goal-directed behavior. As an important modulator of goal-directed behavior, the medial prefrontal cortex was the target of genomic analysis. Rats were trained to self-administer heroin during 3-hour daily sessions for 14 days. Following the self-administration period, rats were reintroduced to the self-administration chambers for a 90-minute extinction session in which they could seek heroin, but received none. The authors found that the behavioral data demonstrated incubation, or increased expression, of heroin-seeking and goal-directed behavior after the 14-day abstinence period. Following 14 days of enforced abstinence, animals displayed heightened drug-seeking behavior when returned to the environment where they had previously received heroin. This increased drug-seeking took place despite the fact that they received no drug during this extinction session. The authors performed whole-genome gene expression analysis and confirmed their results by RT-qPCR. The arrays identified 66 genes whose expression was identified as changed by at least 1.4 fold following 14 days of abstinence and the 90-minute extinction session compared to the saline treated controls. Orthogonal confirmation by RT-qPCR demonstrated significant alterations in several genes.

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Journal: Chembiochem. 2009 Aug 17;10(12):2042-51.

Title: Development of selective bisubstrate-based inhibitors against protein kinase C (PKC) isozymes by using dynamic peptide microarrays.

Authors: A Poot; J van Ameijde; M Slijper; A van den Berg; R Hilhorst; R Ruijtenbeek; R; D Rijkers; R Liskamp

Kinase inhibitors are increasingly important in drug development but because the majority of current inhibitors target the conserved ATP-binding site, selectivity might become an important issue, according to the authors of this paper. This issue could be problematic for the potential drug target protein kinase C, of which 12 isoforms with high homology exist in humans. One strategy to increase selectivity is to prepare bisubstrate-based inhibitors that target the more selective peptide-binding site in addition to the ATP-binding site. In response to this problem, the authors used dynamic peptide microarrays to find peptide-binding site inhibitors. These were linked with chemoselective click chemistry to an ATP-binding site inhibitor, which led to novel bisubstrate structures. The peptide microarrays were then used to evaluate the resulting inhibitors.


Journal: Clinica Chimica Acta. 2009 Aug;406(1-2):31-5.

Title: A fast modified protocol for random-access ultra-high density whole-genome scan: a tool for personalized genomic medicine, positional mapping, and cytogenetic analysis.

Authors: K Lau; C Mak; K Leung; T Tsoi; Y Tang; P Lee; C Lam

The authors describe a modified PCR purification protocol without batch-size limitations for whole-genome scanning using ultra-high density SNP microarrays. Enzyme-digested PCR products were purified with the use of magnetic beads. Separation of the magnetic particles applies magnetic stand devices instead of vacuum pumps. With no batch-size limitation, they genotyped 17 genomic samples and three whole-genome amplified samples in order to examine the performance of the modified protocol. The authors determined their approach offers a sufficient amount of high-quality PCR products for subsequent fragmentation and labeling procedures prior to Affymetrix GeneChip hybridization.


Journal: Genes, Chromosomes, & Cancer. 2009 Aug;48(8):679-93.

Title: LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization.

Authors: S Kresse; H Ohnstad; E Paulsen; B Bjerkehagen; K Szuhai; M Serra; K Schaefer; O Myklebost; L Meza-Zepeda

The authors examined DNA copy number changes in 36 osteosarcoma tumors and 20 cell lines using microarray-based comparative genomic hybridization. They found that the most frequent minimal recurrent regions of gain identified in the tumor samples were in 1q21.2-q21.3, 1q21.3-q22, and 8q22.1. A small region in 3q13.31 containing the gene limbic system-associated membrane protein was frequently deleted. LSAMP has previously been reported to be a candidate tumor suppressor gene in other cancer types. The deletion was validated using fluorescence in situ hybridization, and the expression level and promoter methylation status of LSAMP were investigated using quantitative real-time reverse transcription PCR and methylation-specific PCR, respectively. The authors' results showed that LSAMP is a candidate tumor suppressor gene in osteosarcomas.


Journal: Journal of Allergy and Clinical Immunology. 2009 Aug;124(2):315-22, 322.e1-3.

Title: Development of a novel peptide microarray for large-scale epitope mapping of food allergens.

Authors: J Lin; L Bardina; W Shreffler; D Andreae; Y Ge: J Wang; F Bruni; Z Fu; Y Han; H Sampson

The authors used overlapping peptides of milk allergenic proteins as a model system to develop a peptide microarray-based immunoassay for large-scale epitope mapping of food allergens. Conditions for printing and immunolabeling for the array were optimized using a serum pool of five patients with milk allergy. Reproducibility of the milk peptide microarray was evaluated using replicate arrays immunolabeled with the serum pool, and specificity and sensitivity were assessed by using serial dilution of the serum pool and a peptide inhibition assay. The authors' results show that epitopes identified by the peptide microarray were mostly consistent with those identified previously by SPOT membrane technology. They argue that the peptide microarray could be used in large-scale IgE epitope mapping of milk allergens, as well as epitope mapping of other food allergens.

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Journal: Journal of Pathology. 2009 Aug;218(4):514-9.

Title: Quantitative cell signaling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.

Authors: C Gulmann; K Sheehan; R Conroy; J Wulfkuhle; V Espina; M Mullarkey; E Kay; L Liotta; E Petricoin

In this study, samples from 35 cases of untreated colorectal cancer colectomies were laser capture-microdissected to isolate epithelium and stroma from cancer as well as normal mucosa. Lysates generated from these four tissue types were spotted onto reverse-phase protein microarrays and probed with a panel of antibodies to ERK, p-ERK, p38, p-p38, p-JNK, MEK and p-MEK. While total protein levels were unchanged, or slightly elevated in cancers, activated isoforms, including p-ERK, p-p38 and p-JNK, were decreased two- to four-fold in cancers compared with uninvolved mucosa. These findings were supported by western blotting. The authors concluded that MAPK activity may be down-regulated in colorectal cancer.


Journal: Methods. 2009 Aug;48(4):398-408.

Title: Using ChIP-chip and ChIP-seq to study the regulation of gene expression: genome-wide localization studies reveal widespread regulation of transcription elongation.

Authors: D Gilchrist; D Fargo; K Adelman

The authors describe techniques for coupling ChIP-chip/ChIP-seq with genetic, chemical, and experimental manipulation to obtain mechanistic insight from genome-wide protein-DNA binding studies. The authors used these two techniques to discern immature promoter-proximal RNA polymerase II from productively elongating Pol II, and infer a critical role for the transition between initiation and full elongation competence in regulating development and gene induction in response to environmental signals.


Journal: Molecular & Cellular Proteomics. 2009 Aug;8(8):1765-76.

Title: Identification of novel serological biomarkers for inflammatory bowel disease using Escherichia coli proteome chip.

Authors: C Chen; S Sullivan; T Anderson; A Tan; P Alex; S Brant; C Cuffari; T Bayless; M Talor; C Burek; H Wang; R Li; L Datta; Y Wu; R Winslow; H Zhu; X Li

The authors describe the use of a whole Escherichia coli proteome microarray to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls and clinically well-characterized patients with Crohn's disease and ulcerative colitis. Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Analysis of the microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Of those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm, the authors identified two sets of serum antibodies that were biomarkers for specifically distinguishing CD from healthy controls and CD from UC.


Journal: OMICS. 2009 Aug 10. [Epub ahead of print]

Title: Resampling reveals sample-level differential expression in clinical genome-wide studies.

Authors: Hiissa J, Elo LL, Huhtinen K, Perheentupa A, Poutanen M, Aittokallio T.

The authors introduce ReScore, a resampling-based procedure that aggregates individual changes across all the samples while preserving their clinical classes, and provides multiple sets of markers that can characterize distinct sample subsets. The authors applied ReScore to a public leukemia microarray study to reveal hidden subgroup structures associated with underlying genotypic abnormalities. According to the authors, the procedure improved both the sensitivity and specificity of the findings, as well as helped them to identify several disease subtype-specific genes that have remained undetected in the conventional analyses.


Journal: Oncogene. 2009 Aug 17. [Epub ahead of print]

Title: Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines.

Authors: S Leivonen; R Mäkelä; P Ostling; P Kohonen; S Haapa-Paananen; K Kleivi; E Enerly; A Aakula; K Hellström; N Sahlberg; V Kristensen; A Børresen-Dale; P Saviranta; M Perälä; O Kallioniemi

In this study, the authors used a protein lysate microarray to monitor for target protein levels after high-throughput transfections of 319 pre-miRs into breast cancer cells. They identified 21 miRNAs that downregulated the estrogen receptor-alpha, as validated by western blotting and quantitative real time-PCR, and by demonstrating the inhibition of estrogen-stimulated cell growth. They found evidence of miRNAs inhibiting ERalpha signaling in breast cancer, and demonstrated the high-throughput LMA technology as technique in determining the relative impact of various miRNAs on key target proteins and associated cellular processes and pathways.

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Journal: PLoS One. 2009 Aug 4;4(8):e6511.

Title: GWAS meets microarray: are the results of genome-wide association studies and gene-expression profiling consistent? Prostate cancer as an example.

Authors: I Gorlov; G Gallick; O Gorlova; C Amos; C Logothetis

The authors state that it is "not obvious" whether there is a consistency between the candidate genes identified by genome-wide association studies and those identified by profiling gene expression. They used the Cancer Genetic Markers Susceptibility database to retrieve SNPs from candidate genes for prostate cancer. In addition, they conducted a large meta-analysis of gene expression data in normal prostate and prostate tumor tissue. The authors identified 13,905 genes that were interrogated by both GWAS and microarrays. On the basis of P values from the GWAS, they selected the 1,649 most significantly associated genes for functional annotation by the Database for Annotation, Visualization and Integrated Discovery. They also conducted functional annotation analysis using same number of the top genes identified in the meta-analysis of the gene expression data. The authors found that genes involved in cell adhesion were overrepresented among both the GWAS and microarray genes.


Journal: PLoS One. 2009 Aug 11;4(8):e6569.

Title: Testing and validation of high-density resequencing microarray for broad range biothreat agents detection.

Authors: T Leski; B Lin; A Malanoski; Z Wang; N Long; C Meador; B Barrows; S Ibrahim; J Hardick; M Aitichou; J Schnur; C Tibbetts; D Stenger

The authors designed a broad-range resequencing pathogen microarray for the detection of tropical and emerging infectious agents including biothreat agents. The array is called RPM-TEI. The scope of the RPM-TEI assay enables detection and differential identification of 84 types of pathogens and 13 toxin genes, including most of the class A, B, and C select agents as defined by the Centers for Disease Control and Prevention, according to the authors. Evaluation results showed that the RPM-TEI assay not only detects and identifies agents, but is also able to differentiate near neighbors of the same agent types, such as closely related strains of filoviruses of the Ebola Zaire group, or the Machupo and Lassa arenaviruses, they reported. Also, each RPM-TEI assay results in specimen-specific agent gene sequence information that can be used to assess pathogenicity, mutations, and virulence markers.


Journal: Proceedings of the National Academy of Sciences. 2009 Aug 21. [Epub ahead of print]

Title: Honey bee aggression supports a link between gene regulation and behavioral evolution.

Authors: C Alaux; S Sinha; L Hasadsri; G Hunt; E Guzmán-Novoa; G Degrandi-Hoffman; J Uribe-Rubio; B Southey; S Rodriguez-Zas; G Robinson

The authors studied whether environmental influences on a behavioral phenotype, such as aggression, could have evolved into inherited differences via changes in gene expression. By performing microarray analysis of honey bees, they authors claimed to show that aggression-related genes with inherited patterns of brain expression are also environmentally regulated. Specifically, there were expression differences in the brain for hundreds of genes between the highly aggressive Africanized honey bees compared with European honey bee subspecies. Similar results were obtained for EHB in response to exposure to alarm pheromone, which provokes aggression, and when comparing old and young bees, as aggressive tendencies increase with age. There was significant overlap of the gene lists generated from these three microarray experiments. According to the authors, aggression showed a robust brain molecular signature regardless of whether it occurred because of inherited, age-related, or environmental factors.

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Journal: Proteomics. 2009 Aug 10. [Epub ahead of print]

Title: Requirements for the valid quantification of immunostains on tissue microarray materials using image analysis.

Authors: C Decaestecker; X Moles Lopez; N D'Haene; I Roland; S Guendouz; C Duponchelle; A Berton; O Debeir; I Salmon

This study focuses on practical aspects regarding image acquisition, segmentation of staining and counterstaining areas, and extraction of quantitative features from tissue microarrays. The authors used a commercial system to quantify different immunohistochemistry markers targeting proteins with different expression patterns in colon cancer or brain tumor TMAs. They identified several steps for standardizing computer-assisted immunostaining quantification experiments. Additionally, the authors propose a data normalization process based on reference materials to be able to compare measurements between studies involving different TMAs.


Journal: Psychiatric Genetics. 2009 Aug;19(4):177-85.

Title: Copy number variations associated with idiopathic autism identified by whole-genome microarray-based comparative genomic hybridization.

Authors: S Cho; S Yim; H Yoo; M Kim; G Jung; G Shin; B Kim; J Hwang; J Kang; T Kim; Y Chung

To explore idiopathic autism spectrum disorder-associated copy number variations, the authors conducted a case-control study using whole-genome copy number analysis. Whole-genome microarray-based comparative genomic hybridization was carried out on 28 children diagnosed as ASD and 62 Korean adults without any signs of abnormalities and family history of genetic disorders as normal controls. Fluorescence in situ hybridization and capillary electrophoresis-single-strand conformational polymorphism were used for quantitative verification of the ASD-associated CNVs. The authors identified 38 CNVs. The distributions of copy number loss CNVs on 8p23.1 were found to be significantly different between ASD and control groups. They conclude that their approach can help to elucidate the genetic mechanism of idiopathic ASD.


Journal: Transboundary and Emerging Diseases. 2009 Aug;56(6-7):204-14.

Title: Gene expression profiling of the host response to Mycobacterium bovis infection in cattle.

Authors: D Machugh; E Gormley; S Park; J Browne; M Taraktsoglou; C O'Farrelly; K Meade

The objective of this study was to understand the changing profile of immune responses throughout the course of bovine tuberculosis infection and to identify biomarkers for sensitive diagnosis, particularly during the early stages of infection. The authors believe that transcriptional profiling via microarray and next-generation sequencing may lead to the development of diagnostics for M. bovis infection and the eventual eradication of tuberculosis from cattle populations.

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