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Microanalytical Methods for Bio-Forensics Investigations

Description: Forensics investigations of bio-crime or bio-terrorism incidents require careful analysis of collected evidentiary material. Although the biological markers in the evidentiary material are important (e.g. genomic signatures, protein markers), the elemental make-up of the organisms themselves and the surrounding non-biological material is extremely useful for attributing a specific process and, perhaps, specific persons to the production of the biological agent. This talk will describe the coordinated use of microanalytical techniques such as SEM-EDX, STEM-EDX, and NanoSIMS for generating compositional signatures for bio-forensics investigations. These analytical techniques span length scales from the 50 {micro}m range to the 5nm range. The range of analytical sensitivities spans from {approx}.5wt% for EDX down to parts per billion for SIMS techniques. In addition, we will discuss the use of spectrum imaging techniques for rapidly extracting the key elemental signatures from large scale data sets. Spectrum imaging techniques combined with multivariate statistical analysis allow for the collection and interrogation or enormous quantities of data without pre-biasing the answer.[1] Spectrum imaging has been used successfully in EDX microanalysis[1] (both in the SEM and TEM) and TOF-SIMS[2]. In this study, a set of test biological agents, ?-irradiated Bacillus thuringiensis (Bt), were examined using the aforementioned microanalytical techniques. The sample set included a number of processing conditions to gauge the ability of these techniques to identify the production methods of these simulated agents. Complementary but distinct forensic signatures were obtained by all three analytical techniques. Figure 1 shows two types of silicate particles observed among the spore material itself. At this length scale, the spores themselves cannot be resolved, but the presence of these silicates is key marker for distinguishing this production route. A STEM-EDX spectrum image from the same material does not show these large silicates but instead shows the segregation of elements such as sulfur and silicon ...
Date: February 10, 2006
Creator: Brewer, L N; Weber, P K; Grant, R P; Ghosal, S & Michael, J R
Partner: UNT Libraries Government Documents Department

The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer

Description: Introduction: HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome. Methods: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis. Results: HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression werevalidated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity ...
Date: June 25, 2010
Creator: Hu, Zhi; Huang, Ge; Sadanandam, Anguraj; Gu, Shenda; Lenburg, Marc E; Pai, Melody et al.
Partner: UNT Libraries Government Documents Department

Prediction of epigenetically regulated genes in breast cancer cell lines

Description: Methylation of CpG islands within the DNA promoter regions is one mechanism that leads to aberrant gene expression in cancer. In particular, the abnormal methylation of CpG islands may silence associated genes. Therefore, using high-throughput microarrays to measure CpG island methylation will lead to better understanding of tumor pathobiology and progression, while revealing potentially new biomarkers. We have examined a recently developed high-throughput technology for measuring genome-wide methylation patterns called mTACL. Here, we propose a computational pipeline for integrating gene expression and CpG island methylation profles to identify epigenetically regulated genes for a panel of 45 breast cancer cell lines, which is widely used in the Integrative Cancer Biology Program (ICBP). The pipeline (i) reduces the dimensionality of the methylation data, (ii) associates the reduced methylation data with gene expression data, and (iii) ranks methylation-expression associations according to their epigenetic regulation. Dimensionality reduction is performed in two steps: (i) methylation sites are grouped across the genome to identify regions of interest, and (ii) methylation profles are clustered within each region. Associations between the clustered methylation and the gene expression data sets generate candidate matches within a fxed neighborhood around each gene. Finally, the methylation-expression associations are ranked through a logistic regression, and their significance is quantified through permutation analysis. Our two-step dimensionality reduction compressed 90% of the original data, reducing 137,688 methylation sites to 14,505 clusters. Methylation-expression associations produced 18,312 correspondences, which were used to further analyze epigenetic regulation. Logistic regression was used to identify 58 genes from these correspondences that showed a statistically signifcant negative correlation between methylation profles and gene expression in the panel of breast cancer cell lines. Subnetwork enrichment of these genes has identifed 35 common regulators with 6 or more predicted markers. In addition to identifying epigenetically regulated genes, we show evidence of differentially expressed ...
Date: May 4, 2010
Creator: Loss, Leandro A; Sadanandam, Anguraj; Durinck, Steffen; Nautiyal, Shivani; Flaucher, Diane; Carlton, Victoria EH et al.
Partner: UNT Libraries Government Documents Department

International workshop of chromosome 19

Description: This document summarizes the workshop on physical and genetic mapping of chromosome 19. The first session discussed the major disease loci found on the chromosome. The second session concentrated on reference families, markers and linkage maps. The third session concentrated on radiation hybrid mapping, somatic cell hybrid panels, macro restriction maps and YACs, followed by cDNA and long range physical maps. The fourth session concentrated on compiling consensus genetic and physical maps as well as discussing regions of conflict. The final session dealt with the LLNL cosmid contig database and comparative mapping of homologous regions of the human and mouse genomes, and ended with a discussion of resource sharing. 18 refs., 2 figs. (MHB)
Date: September 16, 1991
Creator: Pericak-Vance, M.A. (Duke Univ. Medical Center, Durham, NC (United States). Div. of Neurology) & Carrano, A.J. (Lawrence Livermore National Lab., CA (United States))
Partner: UNT Libraries Government Documents Department

Tulane/Xavier Center for Bioenvironmental Research; project: hazardous materials in aquatic environments; subproject: biomarkers and risk assessment in Bayou Trepagnier, LA

Description: Tulane and Xavier Universities have singled out the environment as a major strategic focus for research and training for now and beyond the year 2000. the Tulane/Xavier Center for Bioenvironmental Research (CBR) was established in 1989 as the umbrella organization to coordinate environmental research at both universities. CBR projects funded by the DOE under the Hazardous Materials in Aquatic Environments grant are defining the following: (1) the complex interactions that occur during the transport of contaminants through wetlands environments, (2) the actual and potential impact of contaminants on ecological systems and health, (3) the mechanisms and new technologies through which these impacts might be remediated, and (4) new programs aimed at educating and training environmental workers of the future. The subproject described in this report, `Biomarkers and Risk Assessment in Bayou Trepagnier, LN`, is particularly relevant to the US Department of Energy`s Environmental Restoration and Waste Management program aimed at solving problems related to hazard monitoring and clean-up prioritization at sites with aquatic pollution problems in the DOE complex.
Date: December 31, 1996
Creator: Ide, C.
Partner: UNT Libraries Government Documents Department

Use of chromosome translocations for measuring prior environment exposures in humans

Description: Recent advances in cytogenetic methodology are beginning to have a major impact upon our ability to provide assessments of environmental exposure in humans. The advent of fluorescent-based techniques for `painting` whole chromosomes has made the analysis of chromosome translocations rapid, specific, sensitive and routine. Chromosome painting has been used to address a wide variety of scientific questions, resulting in an increased understanding of the biological consequences of adverse environmental exposure. This paper describes the use of chromosome translocations as a biological marker of exposure and effect in humans. The relevance of translocations is discussed, as are the advantages and disadvantages of painting compared to classical cytogenetic methods for translocation evaluation. The factors to consider in the use of translocations as a retrospective indicator of exposure are then described. Several theoretical parameters that are important to the use of translocations are provided, and the paper concludes with a vision for the future of cytogenetic methodology.
Date: May 1, 1997
Creator: Tucker, J. D.
Partner: UNT Libraries Government Documents Department

Rapid, potentially automatable, method extract biomarkers for HPLC/ESI/MS/MS to detect and identify BW agents

Description: The program proposes to concentrate on the rapid recovery of signature biomarkers based on automated high-pressure, high-temperature solvent extraction (ASE) and/or supercritical fluid extraction (SFE) to produce lipids, nucleic acids and proteins sequentially concentrated and purified in minutes with yields especially from microeukaryotes, Gram-positive bacteria and spores. Lipids are extracted in higher proportions greater than classical one-phase, room temperature solvent extraction without major changes in lipid composition. High performance liquid chromatography (HPLC) with or without derivatization, electrospray ionization (ESI) and highly specific detection by mass spectrometry (MS) particularly with (MS){sup n} provides the detection, identification and because the signature lipid biomarkers are both phenotypic as well as genotypic biomarkers, insights into potential infectivity of BW agents. Feasibility has been demonstrated with detection, identification, and determination of infectious potential of Cryptosporidium parvum at the sensitivity of a single oocyst (which is unculturable in vitro) and accurate identification and prediction, pathogenicity, and drug-resistance of Mycobacteria spp.
Date: December 1997
Creator: White, D. C.; Burkhalter, R. S.; Smith, C. & Whitaker, K. W.
Partner: UNT Libraries Government Documents Department

Molecular and cellular markers of toxicity in the Japanese Medaka @

Description: The Japanese Medaka (Oryzias latipes) has been recommended for use as a model organism to detect carcinogenic, teratogenic, cytotoxic, and genotoxic compounds in aquatic systems. Because a long latent period often occurs between initial contact with deleterious chemicals and subsequent expression of the pathology, we are investigating early biologically-relevant responses that can be used as genotoxicity markers of exposure and effect. This project focuses on the development of genotoxic bioassays and experimental protocols for exposing Japanese Medaka to genotoxic compounds. 21 refs., 8 figs, 2 tabs.
Date: January 1, 1990
Creator: Shugart, L.R.; McCarthy, J.F.; D'Surney, S.J.; Greeley, M.S. Jr. & Hull, C.G.
Partner: UNT Libraries Government Documents Department

Phase-sensitive flow cytometry: New technology for analyzing biochemical, functional, and structural features in fluorochrome- labeled cells/particles

Description: Flow cytometry (FCM) instruments rapidly measure biochemical, functional, and cytological properties of individual cells and macromolecular components, e.g., chromosomes, for clinical diagnostic medicine and biomedical and envirorunental research applications. These measurements are based on labeling cells with multiple fluorochromes for correlated analysis of macromolecules, such as DNA RNA, protein, and cell-surface receptors. This report describes the development of a phase-sensitive flow cytometer that provides unique capabilities for making laser-excited, phase-resolved measurements on fluorochrome-labelled cells and particles.
Date: December 1, 1993
Creator: Steinkamp, J. A.
Partner: UNT Libraries Government Documents Department

Biological markers in animals can provide information on exposure and bioavailability of environmental contaminants

Description: Epidemiologic studies of agents present in the environment seek to identify the extent to which they contribute to the causation of a specific toxic, clinical, or pathological endpoint. The multifactorial nature of disease etiology, long latency periods and the complexity of exposure, all contribute to the difficulty of establishing associations and casual relationships between a specific exposure and an adverse outcome. These barriers to studies of exposures and subsequent risk assessment cannot generally be changed. However, the appropriate use of biological markers in animal species living in a contaminated habitat can provide a measure of potential damage from that exposure and, in some instances, act as a surrogate for human environmental exposures. Quantitative predictivity of the effect of exposure to environmental pollutants is being approached by employing an appropriate array of biological end points. 34 refs., 1 fig., 6 tabs.
Date: January 1, 1987
Creator: Shugart, L.R.; Adams, S.M.; Jimenez, B.D.; Talmage, S.S. & McCarthy, J.F.
Partner: UNT Libraries Government Documents Department

Flow cytometry: A powerful technology for measuring biomarkers

Description: A broad definition of a biomarker is that it is a measurable characteristic of a biological system that changes upon exposure to a physical or chemical insult. While the definition can be further refined, it is sufficient for the purposes of demonstrating the advantages of flow cytometry for making quantitative measurements of biomarkers. Flow cytometry and cell sorting technologies have emerged during the past 25 years to take their place alongside other essential tools used in biology such as optical and electron microscopy. This paper describes the basics of flow cytometry technology, provides illustrative examples of applications of the technology in the field of biomarkers, describes recent developments in flow cytometry that have not yet been applied to biomarker measurements, and projects future developments of the technology. The examples of uses of flow cytometry for biomarker quantification cited in this paper are meant to be illustrative and not exhaustive in the sense of providing a review of the field.
Date: September 1, 1994
Creator: Jett, J. H.
Partner: UNT Libraries Government Documents Department

Marker evaluation of human breast and bladder cancers

Description: We are investigating multiple markers in human breast and bladder cancers. Our aim is to identify markers that are clinically relevant and that contribute to our understanding of the disease process in individual patients. Good markers accurately assess the malignant potential of a cancer in an individual patient. Thus, they help identify those cancers that will recur, and they may be used to predict more accurately time to recurrence, response to treatment, and overall prognosis. Therapy and patient management may then be optimized to the individual patient. Relevant markers reflect the underlying pathobiology of individual tumors. As a tissue undergoes transformation from benign to malignant, the cells lose their differentiated phenotype. As a generalization, the more the cellular phenotype, cellular proliferation and cellular genotype depart from normal, the more advanced is the tumor in its biological evolution and the more likely it is that the patient has a poor prognosis. We use three studies to illustrate our investigation of potential tumor markers. Breast cancers are labeled in vivo with 5-bromodeoxyuridine (BrdUrd) to give a direct measure of the tumor labeling index. Bladder cancers are analyzed immunocytochemically using an antibody against proliferation. Finally, the techniques of molecular genetics are used to detect allelic loss in breast cancers. 6 refs., 3 figs.
Date: November 2, 1990
Creator: Mayall, B.H.; Carroll, P.R.; Chen, Ling-Chun; Cohen, M.B.; Goodson, W.H. III; Smith, H.S. et al.
Partner: UNT Libraries Government Documents Department