12 research outputs found
Candidate Serum Biomarkers for Early Intestinal Cancer Using <sup>15</sup>N Metabolic Labeling and Quantitative Proteomics in the <i>Apc</i><sup><i>Min/+</i></sup> Mouse
Current
screening procedures for colorectal cancer are imperfect and highly
invasive and result in increased mortality rates due to low compliance.
The goal of the experiments reported herein is to identify potential
blood-based biomarkers indicative of early stage intestinal cancers
using the <i>Apc</i><sup><i>Min/+</i></sup> mouse
model of intestinal cancer as an experimental system. Serum proteins
from tumor-bearing <i>Apc</i><sup><i>Min/+</i></sup> mice were quantitatively compared to tumor-free <i>Apc</i><sup><i>+/+</i></sup> wild-type mice via <i>in anima</i> metabolic labeling with <sup>14</sup>N/<sup>15</sup>N-labeled Spirulina
algae and an LTQ Orbitrap mass spectrometer. Out of 1116 total serum
proteins quantified, this study identified 40 that were differentially
expressed and correlated with the increase in intestinal neoplasms.
A subset of these differentially expressed proteins underwent a secondary
quantitative screen using selected reaction monitoring-mass spectrometry
with stable isotope-labeled peptides. Using both quantitative techniques,
we identified MGAM and COL1A1 as downregulated and ITIH3 and F5 as
upregulated in serum. All but COL1A1 were similarly differentially
expressed in the mRNA of neoplastic colonic tissues of <i>Apc</i><sup><i>Min/+</i></sup> mice compared to normal wild-type
tissue. These differentially expressed proteins identified in the <i>Apc</i><sup><i>Min/+</i></sup> mouse model have provided
a set of candidate biomarkers for future validation screens in humans
Additional file 6 of Factors influencing and long-term effects of manual myotomy phenomenon during physiotherapy for congenital muscular torticollis
Additional file 6: Supplementary material 2. case tw
Additional file 1 of Factors influencing and long-term effects of manual myotomy phenomenon during physiotherapy for congenital muscular torticollis
Additional file 1: Supplementary Figure 1. Images of the child in Case tw
Additional file 4 of Factors influencing and long-term effects of manual myotomy phenomenon during physiotherapy for congenital muscular torticollis
Additional file 4: Supplementary Table 1. Cheng-Tang rating scores between the MM and NMM group
Additional file 5 of Factors influencing and long-term effects of manual myotomy phenomenon during physiotherapy for congenital muscular torticollis
Additional file 5: Supplementary material 1. case on
An integrated view of colon cancer transcriptional programs provides novel insight into neoplasia
Murine colon tumor adenomas and human CRCs both show adoption and dysregulation of signatures tightly controlled during embryonic mouse colon development. The use of etiologically distinct mouse models of colon cancer allows for the identification of models that resemble different stages of embryonic mouse colon development and that are recapitulated by specific tumor types. All tumors exhibit large-scale activation of developmental patterns. Nuclear β-catenin-positive (and AOM) tumors map more strongly to early development stages during (more proliferative, less differentiated), whereas nuclear β-catenin-negative (and ) tumors map more strongly to later stages consistent with increased epithelial differentiation. Overall representation of the relationship of mouse colon tumor models and human CRC to development and non-developmental expression patterns. Gene expression clusters mapped to the progression of adenomatous and carcinomatous transformation identified in Figures 5 and 6 are shown as the clusters of genes whose expression is either gained or lost associated with the stage of progression. For example normal development could be considered as 'subverted' if there is an absence of expression of genes normally expressed at high level in the developing colon that fail to be expressed in tumors (for example, C18, C19), or that are activated in tumor but not normally expressed in development (C20). Upregulated clusters are enriched for genes with known oncogenic functions and down-regulated clusters for genes associated with tumor suppression. Both mouse colon tumor models and human CRC share in the activation of embryonic colon expression (C22), or partially overlap (C23, dotted lines) the loss or repression of adult differentiation-associated genes (C19), and the loss of tumor suppressor genes (C18). Many human CRCs also lack the expression of additional tumor suppressor programs and gain the expression of oncogenes that are not over-expressed during normal developmental morphogenesis (C21).<p><b>Copyright information:</b></p><p>Taken from "Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer"</p><p>http://genomebiology.com/2007/8/7/R131</p><p>Genome Biology 2007;8(7):R131-R131.</p><p>Published online 5 Jul 2007</p><p>PMCID:PMC2323222.</p><p></p
Stratification of murine colon tumor models by localization of β-catenin and plan for analysis
Colon tumors from four etiologically distinct mouse models of CRC were subjected to microarray gene expression profiling. The gene expression profiles from the different mouse model tumors were compared and contrasted to each other, as well as to those from embryonic mouse colon development and 100 human CRCs.<p><b>Copyright information:</b></p><p>Taken from "Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer"</p><p>http://genomebiology.com/2007/8/7/R131</p><p>Genome Biology 2007;8(7):R131-R131.</p><p>Published online 5 Jul 2007</p><p>PMCID:PMC2323222.</p><p></p
Both human CRCs and mouse colon tumors reactivate an embryonic gene signature
When human and murine tumors are compared, they both broadly re-express an embryonic gene expression pattern. Gene expression profiles from the mouse tumor models and human CRC samples were combined into a single non-redundant gene ortholog genome table structure and subjected to comparative profile analysis. Informative probe-sets from human and mouse platforms were selected, mapped to corresponding ortholog genes, and used to populate a table in which normalized expression for each gene is relative to normal adult colon. Heatmap plot for all cross-species gene orthologs both present and successfully measured on both the Affymetrix Hg-U133 and Vanderbilt Mouse NIA 20 K microarrays (= 8,621 features). This representation suggests that a large number of human CRC signatures exhibit similar behaviors in the mouse tumors and during embryonic mouse colon development (sidebar: 1,080 (red) and 431 (green) gene lists from (b)). Based on results in (a), four separate gene lists were generated with criteria of over- or under-expression in development or over-expression or under-expression in human CRCs (2,718, 2,365, 2,212, and 737, respectively, with the overlaps shown as a sidebar in (a); red, 1,080 transcripts, and green, 431 transcripts). Genes over-expressed and under-expressed in embryonic mouse colon and human CRCs were found to be over-represented as determined by Fisher's exact test analysis (*< 7 × 10, **< 1 × 10, ***< 5 × 10, ****< 1 × 10). Heatmap plot of all genes co-regulated in human CRCs and during early (ED) and late (LD) mouse embryonic colon development (= 2,216 features). Six predominant clusters (C18-C23) characterize the transcriptional relationship between human CRC and mouse colon tumor models and embryonic development. Two clusters (C20 and 21) primarily distinguish human CRCs from murine tumors (A, M, S and T). For example, CRC up-regulated transcripts that are either developmentally up- or down-regulated are represented by cluster C22 (= 860 features) and clusters C21/C23 (= 142 features), respectively. Conversely, CRC down-regulated transcripts that are either down- or up-regulated during development are shown in clusters C18/C19 (= 258 features) and cluster C20 (= 42 features), respectively. Interestingly, while approximately 80% and approximately 60% of genes up- and down-regulated in both human CRCs and mouse development were also up- and down-regulated in tumors from the various mouse models, several clusters provide very interesting exceptions: cluster C20 comprises genes down-regulated in human CRCs that are routinely over-expressed in mouse tumors and development; cluster C21 comprises genes robustly expressed in human CRC that are rarely expressed in embryonic colon or murine tumors. Sample groups: ED, early development (E13.5-E15.5); LD, late development (E16.5-E18.5); A, AOM-induced; M, ; T, ; S, . Tissue groups: AC, adult colon; CRC, human CRC. Staging: nAC, normal colon.<p><b>Copyright information:</b></p><p>Taken from "Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer"</p><p>http://genomebiology.com/2007/8/7/R131</p><p>Genome Biology 2007;8(7):R131-R131.</p><p>Published online 5 Jul 2007</p><p>PMCID:PMC2323222.</p><p></p
All four murine tumor models exhibit reactivation of embryonic gene expression
The expression level of each gene in each sample was calculated relative to that in adult colon. Genes and samples were subjected to unsupervised hierarchical tree clustering for similarities among genes and tumors. Heatmap shows the relative behaviors of 20,393 transcripts that passed basic signal quality filters with gene transcripts shown as separate rows and samples as separate columns. Note that the majority of genes over-expressed in tumors (red) are also over-expressed in embryonic colon; similarly, the genes under-expressed in tumors (blue) are under-expressed in embryonic colon. The color bars to the right indicate the position of 4,693 transcripts over-expressed in both tumors and development (red) or under-expressed in both (green). In addition, there are genes over-expressed in embryonic colon that are under-expressed in tumors and vice versa (asterisks). The genes represented in (a) were divided into those over-expressed and under-expressed in embryonic colon and in the tumors, respectively. Fisher's exact test was used to calculate expected overlaps between lists and confirmed significant over-representation of development-regulated signatures among the tumors (*< 1, **< 1.3, ***< 4, ****< 1). Heatmap showing the behavior of a subset of the transcripts in (a) (= 4,693 features) that were over-expressed in both embryonic colon and tumor samples. Refer to Table 2 for a complete description of the genes associated with these clusters. Embryonic gene expression can be further refined into genes expressed differentially during early (ED; E13.5-15.5) and late (LD; E16.5-18.5) embryonic development. Heatmap showing the relative behaviors of 750 transcripts that are highest-ranked for early versus late embryonic regulation. Overall, transcripts with the highest early embryonic expression were expressed at higher levels in nuclear β-catenin-positive tumors (A and M), whereas nuclear β-catenin-negative tumors (S and T) were representative of later stages of embryonic development. Sample groups: ED, early development (E13.5-E15.5); LD, late development (E16.5-E18.5); A, AOM-induced; M, ; T, ; S, . Staging: nAC, normal colon. Clusters C8-C10 to the right of the heatmap correspond to the K-means functional clusters listed in Table 2.<p><b>Copyright information:</b></p><p>Taken from "Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer"</p><p>http://genomebiology.com/2007/8/7/R131</p><p>Genome Biology 2007;8(7):R131-R131.</p><p>Published online 5 Jul 2007</p><p>PMCID:PMC2323222.</p><p></p
Active canonical WNT signaling (as determined by nuclear β-catenin) stratifies the four murine colon tumor models into two groups
Hierarchical clustering of gene transcripts separates the four models into two groups. The upper panel shows 1,798 gene transcripts identified as differentially expressed among any of the four mouse tumor models (Kruskal-Wallis test + Student-Newman-Keuls test + FDR < 5.10). Results demonstrate that AOM (A) and (M) tumors are transcriptionally more similar to each other than to tumors from (S) and (T) mice. Five clusters have been identified (C1-C5) that correspond to the K-means functional clusters listed in Table 1. Please refer to Table 1 for an in-depth description of the functional classification of the genes found in these clusters. The lower panel illustrates the extent of the similarity between A/M and S/T tumors by identifying the top-ranked 1,265 transcripts of the 1,798 that were higher or lower in the two tumor super-groups (rank based on Wilcoxon-Mann-Whitney test for between-group differences with a FDR < 5.10cutoff). Up-regulated transcripts in A/M tumors are highly enriched for genes associated with canonical WNT signaling activity, cell proliferation, chromatin remodeling, cell cycle progression and mitosis; transcripts over-expressed in S/T tumors are highly enriched for genes related to immune and defense responses, endocytosis, transport, oxidoreductase activity, signal transduction and metabolism. Representative histologies for each of the four tumor models. The lower panel illustrates the model-dependent localization of β-catenin. Tumors from M (bottom left) and A (not shown) mice exhibited prominent nuclear β-catenin accumulation and reduced cell surface staining. Conversely, tumors from S (bottom right) and T(not shown) mice exhibited retention of plasma membrane β-catenin immunoreactivity. A and M in top panel 100× magnification; S and T 200× magnification. M and S in lower panel both 400× magnification.<p><b>Copyright information:</b></p><p>Taken from "Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer"</p><p>http://genomebiology.com/2007/8/7/R131</p><p>Genome Biology 2007;8(7):R131-R131.</p><p>Published online 5 Jul 2007</p><p>PMCID:PMC2323222.</p><p></p