Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis.

Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.

Systematic identification of DNA variants associated with ultraviolet radiation using a novel Geographic-Wide Association Study (GeoWAS).

BACKGROUND: Long-term environmental variables are widely understood to play important roles in DNA variation. Previously, clinical studies examining the impacts of these variables on the human genome were localized to a single country, and used preselected DNA variants. Furthermore, clinical studies or surveys are either not available or difficult to carry out for developing countries. A systematic approach utilizing bioinformatics to identify associations among environmental variables, genetic variation, and diseases across various geographical locations is needed but has been lacking. METHODS: Using a novel Geographic-Wide Association Study (GeoWAS) methodology, we identified Single Nucleotide Polymorphisms (SNPs) in the Human Genome Diversity Project (HGDP) with population allele frequencies associated geographical ultraviolet radiation exposure, and then assessed the diseases known to be assigned with these SNPs. RESULTS: 2,857 radiation SNPs were identified from over 650,000 SNPs in 52 indigenous populations across the world. Using a quantitative disease-SNP database curated from 5,065 human genetic papers, we identified disease associations with those radiation SNPs. The correlation of the rs16891982 SNP in the SLC45A2 gene with melanoma was used as a case study for analysis of disease risk, and the results were consistent with the incidence and mortality rates of melanoma in published scientific literature. Finally, by analyzing the ontology of genes in which the radiation SNPs were significantly enriched, potential associations between SNPs and neurological disorders such as Alzheimer's disease were hypothesized. CONCLUSION: A systematic approach using GeoWAS has enabled us to identify DNA variation associated with ultraviolet radiation and their connections to diseases such as skin cancers. Our analyses have led to a better understating at the genetic level of why certain diseases are more predominant in specific geographical locations, due to the interactions between environmental variables such as ultraviolet radiation and the population types in those regions. The hypotheses proposed in GeoWAS can lead to future testing and interdisciplinary research.

Document-level classification of CT pulmonary angiography reports based on an extension of the ConText algorithm.

In this paper we describe an application called peFinder for document-level classification of CT pulmonary angiography reports. peFinder is based on a generalized version of the ConText algorithm, a simple text processing algorithm for identifying features in clinical report documents. peFinder was used to answer questions about the disease state (pulmonary emboli present or absent), the certainty state of the diagnosis (uncertainty present or absent), the temporal state of an identified pulmonary embolus (acute or chronic), and the technical quality state of the exam (diagnostic or not diagnostic). Gold standard answers for each question were determined from the consensus classifications of three human annotators. peFinder results were compared to naive Bayes' classifiers using unigrams and bigrams. The sensitivities (and positive predictive values) for peFinder were 0.98(0.83), 0.86(0.96), 0.94(0.93), and 0.60(0.90) for disease state, quality state, certainty state, and temporal state respectively, compared to 0.68(0.77), 0.67(0.87), 0.62(0.82), and 0.04(0.25) for the naive Bayes' classifier using unigrams, and 0.75(0.79), 0.52(0.69), 0.59(0.84), and 0.04(0.25) for the naive Bayes' classifier using bigrams.

TMA-TAB: a spreadsheet-based document for exchange of tissue microarray data based on the tissue microarray-object model.

The importance of tissue microarrays (TMA) as clinical validation tools for cDNA microarray results is increasing, whereas researchers are still suffering from TMA data management issues. After we developed a comprehensive data model for TMA data storage, exchange and analysis, TMA-OM, we focused our attention on the development of a user-friendly exchange format with high expressivity in order to promote data communication of TMA results and TMA-OM supportive database applications. We developed TMA-TAB, a spreadsheet-based data format for TMA data submission to the TMA-OM supportive TMA database system. TMA-TAB was developed by simplifying, modifying and reorganizing classes, attributes and templates of TMA-OM into five entities: experiment, block, slide, core_in_block, and core_in_slide. Five tab-delimited formats (investigation design format, block description format, slide description format, core clinicohistopathological data format, and core result data format) were made, each representing the entities of experiment, block, slide, core_in_block, and core_in_slide. We implemented TMA-TAB import and export modules on Xperanto-TMA, a TMA-OM supportive database application, to facilitate data submission. Development and implementation of TMA-TAB and TMA-OM provide a strong infrastructure for powerful and user-friendly TMA data management.

Coanalysis of GWAS with eQTLs reveals disease-tissue associations.

Expression quantitative trait loci (eQTL), or genetic variants associated with changes in gene expression, have the potential to assist in interpreting results of genome-wide association studies (GWAS). eQTLs also have varying degrees of tissue specificity. By correlating the statistical significance of eQTLs mapped in various tissue types to their odds ratios reported in a large GWAS by the Wellcome Trust Case Control Consortium (WTCCC), we discovered that there is a significant association between diseases studied genetically and their relevant tissues. This suggests that eQTL data sets can be used to determine tissues that play a role in the pathogenesis of a disease, thereby highlighting these tissue types for further post-GWAS functional studies.

Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals.

Massively parallel sequencing technologies have identified a broad spectrum of human genome diversity. Here we deep sequenced and correlated 18 genomes and 17 transcriptomes of unrelated Korean individuals. This has allowed us to construct a genome-wide map of common and rare variants and also identify variants formed during DNA-RNA transcription. We identified 9.56 million genomic variants, 23.2% of which appear to be previously unidentified. From transcriptome sequencing, we discovered 4,414 transcripts not previously annotated. Finally, we revealed 1,809 sites of transcriptional base modification, where the transcriptional landscape is different from the corresponding genomic sequences, and 580 sites of allele-specific expression. Our findings suggest that a considerable number of unexplored genomic variants still remain to be identified in the human genome, and that the integrated analysis of genome and transcriptome sequencing is powerful for understanding the diversity and functional aspects of human genomic variants.

Experience with voice recognition in surgical pathology at a large academic multi-institutional center.

There are few reports of institutional use of voice recognition technology in clinical practice. We describe our experience with voice recognition-integrated synoptic-like dictation, associating templates with key spoken phrases, that we have used in gross examination of common specimens and as a major component of our workflow since 2001. The primary application is VoiceOver Enterprise (Voicebrook, Lake Success, NY), which uses Dragon NaturallySpeaking Medical Edition (Nuance Communications, Burlington, MA) as its speech engine. This integrates with the anatomic pathology laboratory information system (APLIS) and other applications, such as Microsoft Office (Microsoft, Redmond, WA). The largest user group, pathology assistants, mainly dictates biopsy reports, numbering approximately 210,000 specimens since 2001. The technology has been useful in our anatomic pathology workflow and provided a good return on investment, including marked improvements in turnaround time, results standardization, error reduction, and cost savings. The most helpful features of the software are templating, the seamless integration with APLIS, and the voice command creation tools.

Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing.

Copy number variants (CNVs) account for the majority of human genomic diversity in terms of base coverage. Here, we have developed and applied a new method to combine high-resolution array comparative genomic hybridization (CGH) data with whole-genome DNA sequencing data to obtain a comprehensive catalog of common CNVs in Asian individuals. The genomes of 30 individuals from three Asian populations (Korean, Chinese and Japanese) were interrogated with an ultra-high-resolution array CGH platform containing 24 million probes. Whole-genome sequencing data from a reference genome (NA10851, with 28.3x coverage) and two Asian genomes (AK1, with 27.8x coverage and AK2, with 32.0x coverage) were used to transform the relative copy number information obtained from array CGH experiments into absolute copy number values. We discovered 5,177 CNVs, of which 3,547 were putative Asian-specific CNVs. These common CNVs in Asian populations will be a useful resource for subsequent genetic studies in these populations, and the new method of calling absolute CNVs will be essential for applying CNV data to personalized medicine.

Stability of repetitive-sequence PCR patterns with respect to culture age and subculture frequency.

To examine the stability of repetitive-sequence (rep) PCR profiles, six species of bacteria were subcultured to blood agar plates and DNA was extracted from the cultures after 24, 48, and 72 h of incubation at 35 degrees C. In addition, the same species were subcultured to fresh blood plates daily and DNA was extracted from the cultures after growth of 5, 10, and 15 subcultures, respectively. rep PCR analysis demonstrated that all rep PCR fingerprints from a single species were identical.

Model for predicting the impact of gadolinium on plasma calcium measured by the o-cresolphthalein method.

BACKGROUND: Gadolinium formulations, which are administered as contrast agents in magnetic resonance imaging examinations, interfere with colorimetric serum calcium determinations. METHODS: We performed an in vitro study to determine the extent to which three gadolinium formulations-gadodiamide (Omniscan), gadopentetate dimeglumine (Magnevist), and gadoversetamide (OptiMARK)-affect measurements by two methods that use o-cresolphthalein (Dade Behring, Inc. and Roche Diagnostics) and one that uses arsenazo dye (Equal Diagnostics). We also compared values from the o-cresolphthalein methods for 116 samples from patients administered gadodiamide. RESULTS: Magnevist did not affect any of the methods evaluated, whereas Omniscan and OptiMARK were identical in their effects. For the Dade method, the differences from the control sample were < or =4.0 and 7.0 mg/L at 0.25 and 0.5 mmol/L gadolinium, respectively. For the Roche method, the differences were 19, 9.0, and 5.0 mg/L at 0.5, 0.25, and 0.125 mmol/L gadolinium, respectively. Falsely increased calcium values were seen when samples were measured by the arsenazo-based method: differences were 6.0 and 3.0 mg/L at 1.0 and 0.5 mmol/L gadolinium. Using patient data collected at our institution, we were able to generate a model for predicting, from a patient's glomerular filtration rate and the time elapsed since administration, the impact of Omniscan on calcium measurements by the o-cresolphthalein method from Roche Diagnostics. CONCLUSIONS: The predictive model can be used to calculate, in patients who have received gadodiamide, the minimum length of time to wait before blood collection to avoid pseudohypocalcemia when the Roche o-cresolphthalein method is used.