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(2006) Hitchins, Megan; Suter, C; Wong, Jenny; Cheong, Kay; Hawkins, Nicholas; Leggett, B; Scott, R; Spigelman, Allan; Tomlinson, Ian; Martin, David; Ward, RobynJournal Article
(2003) Welsh, John; Sapinoso, Lisa; Kern, Suzanne; Brown, David; Liu, Tao; Bauskin, Asne; Ward, Robyn; Hawkins, Nicholas; Quinn, David; Russell, Pamela; Sutherland, Robert; Breit, Samuel; Moskaluk, Christopher; Frierson Jr, Henry; Hampton, GarretJournal ArticleGenetic alterations in tumor cells often lead to the emergence of growth-stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited for cancer diagnosis and management or as points of therapeutic intervention. Here, we combined the use of controlled vocabulary terms and sequence-based algorithms to predict genes encoding secreted proteins from among ≈12,500 sequences represented on oligonucleotide microarrays. Expression of these genes was queried in 150 carcinomas from 10 anatomic sites of origin and compared with 46 normal tissues derived from the corresponding sites of tumor origin and other body tissues and organs. Of 74 different genes identified as overexpressed in cancer tissues, several encode proteins with demonstrated clinical diagnostic application, such as α-fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or therapeutic utility, such as gastrin-releasing peptide/bombesin in lung carcinomas. We show that several of the other candidate genes encode proteins with high levels of tumor-associated expression by immunohistochemistry on tissue microarrays and further demonstrate significantly elevated levels of another novel candidate protein, macrophage inhibitory cytokine 1, a distant member of the tranforming growth factor-β superfamily, in the serum of patients with metastatic prostate, breast, and colorectal carcinomas. Our results suggest that the combination of annotation/protein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to other human diseases.
(2003) Brown, David; Ward, Robyn; Buckhaults, Philip; Liu, Tao; Romans, Katherine; Hawkins, Nicholas; Bauskin, Asne; Kinzler, Kenneth; Vogelstein, Bert; Breit, SamuelJournal ArticlePurpose: Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor ß (TGF-ß) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia. Experimental Design: We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures. Results: MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes. Conclusions: This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.
(2008) Shen, Yansong; Guo, Baoyu; Yu, Aibing; Maldonado, Daniel; Austin, Patricia; Zulli, PaulJournal ArticlePulverized coal injection technology is widely used in blast furnace ironmaking due to economic, operational and environmental benefits. High burnout within the tuyere and raceway is required for high coal injection rate operation. In order to analyze the flow and combustion in the tuyere and raceway more accurately and reliably, a three-dimensional model of coal combustion is developed. This model is validated against the measurements from two pilot scale test rigs in terms of gas species composition and coal burnout. The gas-solid flow and coal combustion are simulated and analysed. The results indicate that compared to our previous model, the present model is able to provide more detailed gas species distributions and better describe the evolutions of coal particles. It is more sensitive to various parameters and hence more robust in examining various blast furnace operations.
Exonuclease activity and P nucleotide addition in the generation of the expressed immunoglobulin repertoire(2004) Jackson, Katherine; Gaeta, Bruno; Sewell, William; Collins, AndrewJournal ArticleBACKGROUND: Immunoglobulin rearrangement involves random and imprecise processes that act to both create and constrain diversity. Two such processes are the loss of nucleotides through the action of unknown exonuclease(s) and the addition of P nucleotides. The study of such processes has been compromised by difficulties in reliably aligning immunoglobulin genes and in the partitioning of nucleotides between segment ends, and between N and P nucleotides. RESULTS: A dataset of 294 human IgM sequences was created and partitioned with the aid of a probabilistic model. Non-random removal of nucleotides is seen between the three IGH gene types with the IGHV gene averaging removals of 1.2 nucleotides compared to 4.7 for the other gene ends (p < 0.001). Individual IGHV, IGHD and IGHJ gene subgroups also display statistical differences in the level of nucleotide loss. For example, within the IGHJ group, IGHJ3 has average removals of 1.3 nucleotides compared to 6.4 nucleotides for IGHJ6 genes (p < 0.002). Analysis of putative P nucleotides within the IgM and pooled datasets revealed only a single putative P nucleotide motif (GTT at the 3` D-REGION end) to occur at a frequency significantly higher then would be expected from random N nucleotide addition. CONCLUSIONS: The loss of nucleotides due to the action of exonucleases is not random, but is influenced by the nucleotide composition of the genes. P nucleotides do not make a significant contribution to diversity of immunoglobulin sequences. Although palindromic sequences are present in 10% of immunologlobulin rearrangements, most of the `palindromic` nucleotides are likely to have been inserted into the junction during the process of N nucleotide addition. P nucleotides can only be stated with confidence to contribute to diversity of less than 1% of sequences. Any attempt to identify P nucleotides in immunoglobulins is therefore likely to introduce errors into the partitioning of such sequences. [Journal Article; In English;
Reconsidering the human immunoglobulin heavy-chain locus: 1. An evaluation of the expressed human IGHD gene repertoire(2006) Lee, Cathryn; Gaeta, Bruno; Malming, H; Bain, Michael; Sewell, William; Collins, AndrewJournal ArticleWe have used a bioinformatics approach to evaluate the completeness and functionality of the reported human immunoglobulin heavy-chain IGHD gene repertoire. Using the hidden Markov-model-based iHMMune-align program, 1,080 relatively unmutated heavy-chain sequences were aligned against the reported repertoire. These alignments were compared with alignments to 1,639 more highly mutated sequences. Comparisons of the frequencies of gene utilization in the two databases, and analysis of features of aligned IGHD gene segments, including their length, the frequency with which they appear to mutate, and the frequency with which specific mutations were seen, were used to determine the reliability of alignments to the less commonly seen IGHD genes. Analysis demonstrates that IGHD4-23 and IGHD5-24, which have been reported to be open reading frames of uncertain functionality, are represented in the expressed gene repertoire; however, the functionality of IGHD6-25 must be questioned. Sequence similarities make the unequivocal identification of members of the IGHD1 gene family problematic, although all genes except IGHD1-14*01 appear to be functional. On the other hand, reported allelic variants of IGHD2-2 and of the IGHD3 gene family appear to be nonfunctional, very rare, or nonexistent. Analysis also suggests that the reported repertoire is relatively complete, although one new putative polymorphism (IGHD3-10*p03) was identified. This study therefore confirms a surprising lack of diversity in the available IGHD gene repertoire, and restriction of the germline sequence databases to the functional set described here will substantially improve the accuracy of IGHD gene alignments and therefore the accuracy of analysis of the V-D-J junction.