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Biomedical subjects

Edison T Liu

Publications and source records attributed to Edison T Liu.

At least 73 records · Page 4Linked to original sources
PubMed2004

Detection of severe acute respiratory syndrome coronavirus in blood of infected patients.

Severe acute respiratory syndrome (SARS) has caused major outbreaks worldwide, resulting in an urgent need to obtain sensitive and accurate diagnosis of this disease. PCR-based detection methods were developed for use on a variety of samples, including blood. Eighteen subjects were investigated, and results indicated that blood samples contain sufficient virus for detection by using quantitative real-time PCR.

Humans↗
PubMed2004

Expression genomics and cancer biology.

Expression genomics is a term that is used to describe the investigation of transcription in a whole-genome manner and includes the investigation of gene regulation. Characteristic of this approach is its comprehensiveness and the highly multiplexed nature of its analysis. Thus, the range of technologies used include microarrays, tag library approaches, such as serial analysis of gene expression (SAGE), full-length cDNA cloning and sequencing, and chromatin immunoprecipitation coupled with cloning/sequencing or applied to genomic chips. These technologies are all complementary since they have different capabilities and attack different components of the transcriptome: transcriptional regulation, promoter usage, differential splicing, and gene expression. Unlike genome sequencing, the combinatorial complexity of the transcriptome is immense, making its complete characterization impossible. Instead, the strategy has shifted to the analysis of the whole transcriptome in a context-driven, cell biological framework where the fundamental truths emerge through multiple comparisons and pharmacological challenges. The density of non-redundant data generated with any experiment allows for the assessment of higher order relationships. This comprehensive data, in turn, permits information convergence across different experiments, organisms, and data sets. Surprising concordance in the underlying conclusions is observed with data of such complexity. Since microarrays have been the most widely used technology in expression genomics for the study of cancer biology, this paper will focus on studies using expression arrays, but will also touch on other transcriptome-directed technologies. The experience with these approaches is sufficiently mature to arrive at some generalizable observations. First, although expression genomics is a useful approach for the discovery of individual candidate genes, its greatest power is in defining class distinctions using the collective behavior of gene clusters. Therefore, expression genomic output can effectively uncover hierarchies of molecular importance. Second, in the hierarchy of factors that determine the expression footprint within a cell, cell lineage is the most important, followed by the activity of specific biochemical pathways and further followed by the effect of individual genes. Lastly, expression profiling is an effective clinical tool that can discern prognostic and therapeutic classes. The importance of these gene lists is that not only do they describe potential therapeutic targets, but they are effective monitors of therapeutic efficacy.

Animals↗
PubMed2004

Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals.

The liver X receptors alpha and beta (LXRalpha and LXRbeta ) are members of the nuclear receptor superfamily of proteins which are highly expressed in metabolically active tissues. They regulate gene expression of critical genes involved in cholesterol catabolism and transport, lipid and triglyceride biosynthesis and carbohydrate metabolism in response to distinct oxysterols and intermediates in the cholesterol metabolic pathway. The biological roles of the LXRs in tissues other than liver, intestine and adipose tissue are poorly elucidated. In this study we used global gene-expression profiling analysis to detect differences in expression patterns in several tissues from mice fed an LXR agonist or vehicle. Our results show that LXR plays an important role in the kidney, lung, adrenals, brain, testis and heart where several putative LXR target genes were found. The effects of the LXRs were further analysed in adrenals where treatment with an LXR agonist induced expression of adrenocorticotrophic hormone receptor, suppressed expression of uncoupling protein (UCP)-1 and UCP-3 as well as several glycolytic enzymes and led to increased serum corticosterone levels. These results indicate novel biological roles of the LXR including regulation of energy metabolism, glycolysis and steroidogenesis in the adrenals via alteration of expression profiles of putative target genes.

Adrenal Glands↗
PubMed2004

Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts.

We have investigated gene expression profiles of human ovarian carcinomas in vivo during Taxol(R) (paclitaxel) treatment and observed a difference in expression. Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg/kg of paclitaxel. Therapeutic efficacy was achieved for 1A9, while 1A9PTX22 did not respond. Tumor tissues harvested 4 and 24 h after treatment were evaluated by cDNA microarray against untreated tumors. Paclitaxel caused the modulation of more genes in 1A9 than in 1A9PTX22 tumors, in accordance to their therapeutic response. Most gene expression alterations were detected 24 h after paclitaxel administration and affected genes involved in various biological functions including cell cycle regulation and cell proliferation (CDC2, CDKN1A, PLAB, and TOP2A), apoptosis (BNIP3 and PIG8), signal transduction and transcriptional regulation (ARF1, ATF2, FOS, GNA11, HDAC3, MADH2, SLUG, and SPRY4), fatty acid biosynthesis and sterol metabolism (FDPS, IDI1, LIPA, and SC5D), and IFN-mediated signaling (G1P3, IFI16, IFI27, IFITM1, and ISG15). The modulation of two representative genes, CDKN1A and TOP2A, was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel. We found that the changes in expression level of these genes was strictly associated with the responsiveness to paclitaxel. Our study shows the feasibility of obtaining gene expression profiles of xenografted tumor models as a result of drug exposure. This in turn might provide insights related to the drugs' action in vivo that will anticipate the response to treatment manifested by tumors and could be the basis for novel approaches to molecular pharmacodynamics.

Animals↗
PubMed2003

Breast cancer classification and prognosis based on gene expression profiles from a population-based study.

Comprehensive gene expression patterns generated from cDNA microarrays were correlated with detailed clinico-pathological characteristics and clinical outcome in an unselected group of 99 node-negative and node-positive breast cancer patients. Gene expression patterns were found to be strongly associated with estrogen receptor (ER) status and moderately associated with grade, but not associated with menopausal status, nodal status, or tumor size. Hierarchical cluster analysis segregated the tumors into two main groups based on their ER status, which correlated well with basal and luminal characteristics. Cox proportional hazards regression analysis identified 16 genes that were significantly associated with relapse-free survival at a stringent significance level of 0.001 to account for multiple comparisons. Of 231 genes previously reported by others [van't Veer, L. J., et al. (2002) Nature 415, 530-536] as being associated with survival, 93 probe elements overlapped with the set of 7,650 probe elements represented on the arrays used in this study. Hierarchical cluster analysis based on the set of 93 probe elements segregated our population into two distinct subgroups with different relapse-free survival (P < 0.03). The number of these 93 probe elements showing significant univariate association with relapse-free survival (P < 0.05) in the present study was 14, representing 11 unique genes. Genes involved in cell cycle, DNA replication, and chromosomal stability were consistently elevated in the various poor prognostic groups. In addition, glutathione S-transferase M3 emerged as an important survival marker in both studies. When taken together with other array studies, our results highlight the consistent biological and clinical associations with gene expression profiles.

Breast Neoplasms↗
PubMed2003

Dragon ERE Finder version 2: A tool for accurate detection and analysis of estrogen response elements in vertebrate genomes.

We present a unique program for identification of estrogen response elements (EREs) in genomic DNA and related analyses. The detection algorithm was tested on several large datasets and makes one prediction in 13 300 nt while achieving a sensitivity of 83%. Users can further investigate selected regions around the identified ERE patterns for transcription factor binding sites based on the TRANSFAC database. It is also possible to search for candidate human genes with a match for the identified EREs and their flanking regions within EPD annotated promoters. Additionally, users can search among the extended promoter regions of approximately 11 000 human genes for those that have a high degree of similarity to the identified ERE patterns. Dragon ERE Finder version 2 is freely available for academic and non-profit users (http://sdmc.lit.org.sg/ERE-V2/index).

Algorithms↗
PubMed2003

Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection.

BACKGROUND: The cause of severe acute respiratory syndrome (SARS) has been identified as a new coronavirus. Whole genome sequence analysis of various isolates might provide an indication of potential strain differences of this new virus. Moreover, mutation analysis will help to develop effective vaccines. METHODS: We sequenced the entire SARS viral genome of cultured isolates from the index case (SIN2500) presenting in Singapore, from three primary contacts (SIN2774, SIN2748, and SIN2677), and one secondary contact (SIN2679). These sequences were compared with the isolates from Canada (TOR2), Hong Kong (CUHK-W1 and HKU39849), Hanoi (URBANI), Guangzhou (GZ01), and Beijing (BJ01, BJ02, BJ03, BJ04). FINDINGS: We identified 129 sequence variations among the 14 isolates, with 16 recurrent variant sequences. Common variant sequences at four loci define two distinct genotypes of the SARS virus. One genotype was linked with infections originating in Hotel M in Hong Kong, the second contained isolates from Hong Kong, Guangzhou, and Beijing with no association with Hotel M (p<0.0001). Moreover, other common sequence variants further distinguished the geographical origins of the isolates, especially between Singapore and Beijing. INTERPRETATION: Despite the recent onset of the SARS epidemic, genetic signatures are emerging that partition the worldwide SARS viral isolates into groups on the basis of contact source history and geography. These signatures can be used to trace sources of infection. In addition, a common variant associated with a non-conservative aminoacid change in the S1 region of the spike protein, suggests that immunological pressures might be starting to influence the evolution of the SARS virus in human populations.

Amino Acid Sequence↗
PubMed2003

Breast cancer cell line proliferation blocked by the Src-related Rak tyrosine kinase.

Rak is a 54 kDa protein tyrosine kinase originally isolated from breast cancer cells and expressed in epithelial cells. It resembles the protooncogene Src structurally but lacks an amino-terminal myristylation site and localizes to the nuclear and perinuclear regions of the cell. We report here that expression of Rak in 2 different breast cancer cell lines inhibits growth and causes G(1) arrest of the cell cycle. This growth inhibition is kinase-dependent but does not require the Rak SH2 or SH3 domain. Rak also binds to the pRb tumor-suppressor protein but inhibits growth even in cells that lack pRb. These results suggest that Rak regulates cell growth by phosphorylating perinuclear proteins and has a function that is distinct from the Src-related kinase family.

Blotting, Western↗
PubMed2003

Molecular determinants of tumor differentiation in papillary serous ovarian carcinoma.

In epithelial ovarian cancer, tumor grade is an independent prognosticator whose molecular determinants remain unknown. We investigated patterns of gene expression in well- and poorly differentiated serous papillary ovarian and peritoneal carcinomas with cDNA microarrays. A 6500-feature cDNA microarray was used for comparison of the molecular profiles of eight grade III and four grade I stage III serous papillary adenocarcinomas. With a modified F-test in conjunction with random permutations, 99 genes whose expression was significantly different between grade I and grade III tumors were identified (P < 0.01). A disproportionate number of these differentially expressed genes were located on the chromosomal regions 20q13 and all exhibited higher expression in grade III tumors. Interphase fluorescent in situ hybridization demonstrated 20q13 amplification in two of the four grade III and none of the three grade I tumors available for evaluation. Several centrosome-related genes also showed higher expression in grade III tumors. We propose a model in which tumor differentiation is inversely correlated with the overexpression of several oncogenes located on 20q13, a common amplicon in ovarian and numerous other cancers. Dysregulation of centrosome function is one potential mechanistic link between genetic/epigenetic changes and the poorly differentiated phenotype in ovarian cancer.

Biomarkers, Tumor↗
PubMed2003

Molecular profiles of invasive mucinous and ductal carcinomas of the breast: a molecular case study.

Expression profiling using cDNA microarrays have redefined the molecular classification of some cancers. The comprehensive genetic analysis also permits the identification of novel pathways that might determine subtle differences in tumor phenotype. Herein, we analyzed the tissues from a patient with bilateral cancer of different histologies in each breast (pure invasive mucinous and pure invasive ductal), thus providing a unique opportunity to assess the expression profiles determined by histology in an isogenic human background. Our results show that the mucinous phenotype is associated with the expression of immunostimulatory and inhibitory genes, consistent with the cellular infiltration of lymphocytes and with the expression of enzymes involved in mucin production. Moreover, the panel of matrix metallo-proteinases are distinctly different between the mucinous and the invasive tumors, suggesting that therapeutic targets to this class of compounds may need to be tailored for the varying histologies. Taken together, these data suggest that expression profiling can be used diagnostically to distinguish individual histologic subclassifications and may guide the selection of target therapeutics.

Adenocarcinoma, Mucinous↗
PubMed2003

Classification of cancers by expression profiling.

Expression profiling using microarray technology has refined the classification of cancer. The greatest advances have been in lymphomas, leukaemias, and breast cancer where array information identified new diagnostic categories not achievable by standard microscopic or molecular means. These sub-categories often have distinct prognostic profiles. The same investigations have clarified the cellular lineage of cancer types, highlighted the importance of biochemical pathways in determining the expression 'phenotype', and identified potential new diagnostic markers and therapeutic targets.

Animals↗
PubMed2003

HER-2/neu and topoisomerase IIalpha in breast cancer.

In breast cancer, the predominant genetic mechanism for oncogene activation is through an amplification of a gene. The HER-2 (also known as ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer, and its overexpression is associated with poor clinical outcome. In addition to its important role in breast cancer growth and progression, HER-2 is also a target for a new form of chemotherapy. Breast cancer patients have been treated with considerable success since 1998 with trastuzumab, a recombinant antibody designed to block signaling through HER-2 receptor. HER-2 has also been implicated in altering the chemosensitivity of breast cancer cells to different forms of conventional cytotoxic chemotherapy, particularly of topoII-inhibitors (e.g., anthracyclines). Topoisomerase IIalpha gene is located just by the HER-2 oncogene at the chromosome 17q12-q21 and is amplified or deleted in almost 90% of the HER-2 amplified primary breast tumors. Recent data suggests that amplification and deletion of topoisomerase IIalpha may account for both relative chemosensitivity and resistance to anthracycline therapy, depending on the specific genetic defect at the topoIIalpha locus. Expanding our understanding of HER-2 amplification also changes its role in the pathogenesis of breast cancer. HER-2 is an oncogene that clearly can drive tumor induction and growth and is also a target for a new kind of chemotherapy, but its function as a marker for chemoselection may be due to associated genetic changes, of which topoisomerase IIalpha is a good example. Moreover, despite potential evidence that genes other than HER-2, such as topoisomerase IIalpha, may be more important predictors of therapeutic response in breast cancer, HER-2 status still has a very significant role in therapeutic selection, mainly as the major criterion for administering trastuzumab in treating breast cancer. Thus, the clinical and therapeutic importance of the HER-2 and topoisomerase IIalpha status to breast cancer management should only increase in the next few years.

Antibodies, Monoclonal↗
PubMed2003

Strategy for the design of custom cDNA microarrays.

DNA microarrays are valuable but expensive tools for expression profiling of cells, tissues, and organs. The design of custom microarrays leads to cost reduction without necessarily compromising their biological value. Here we present a strategy for designing custom cDNA microarrays and constructed a microarray for mouse immunology research (ImmunoChip). The strategy used interrogates expressed sequence tag databases available in the public domain but overcomes many of the problems encountered. Immunologically relevant clusters were selected based on the expression of expressed sequence tags in relevant libraries. Selected clusters were organized in modules, and the best representative clones were identified. When tested, this microarray was found to have minimal clone identity errors or phage contamination and identified molecular signatures of lymphoid cell lines. Our proposed design of custom microarrays avoids probe redundancy, allows the organization of the chip to optimize chip production, and reduces microarray production costs. The strategy described is also useful for the design of oligonucleotide microarrays.

Animals↗
PubMed2003

HER-2/neu and topoisomerase IIalpha--simultaneous drug targets in cancer.

In solid tumors the predominant genetic mechanism for oncogene activation is through amplification of genes. The HER-2 (also known as ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also commonly amplified in other forms of cancer. Alongside its important role in tumor induction, growth and progression, HER-2 is also a target for a new form of chemotherapy. Since 1998, breast cancer patients have been treated with considerable success with Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, a large number of various HER-2 directed immunological and genetic approaches, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) together, have demonstrated promising pre-clinical potential towards HER-2 amplified carcinomas. Moreover, the HER-2 amplicon contains other genes with altered copy numbers that could be used as targets for chemotherapy. The topoisomerase IIalpha (topoIIalpha) gene (TOP2A) is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted, with equal frequency, in almost 90% of HER-2 amplified primary breast tumors. Recent data suggest that amplification or deletion of TOP2A may account for both sensitivity or resistance to topoII-inhibitor-chemotherapy, depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding. The number of therapeutic strategies targeting HER-2 signaling pathways will most probably be introduced in the treatment of HER-2 amplified tumors within the next few years. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostics tests such as those ascertaining topoIIalpha status, may be helpful for the ideal selection of patients for the combination therapy of a HER-2 targeting drug together with a cytotoxic drug. The clinical and therapeutic importance of the HER-2 and TOPO2A status of tumor cells in cancer management will only increase within the next few years.

Antigens, Neoplasm↗