Expression Patterns of Hoxa4 and Meis1 Genes Are Regulated by Promoter Hypermethylation and When Combined Predict Survival in AML.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1204-1204
Author(s):  
Lykke Christina Grubach ◽  
Mike Zangenberg ◽  
Hans Beier Ommen ◽  
Anni Aggerholm ◽  
Peter Hokland
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Expression Patterns ◽  
Group Identification ◽  
Normal Karyotype ◽  
Promoter Hypermethylation ◽  
Melting Curve Analysis ◽  
Altered Expression ◽  
Expression Levels ◽  
Prognostic Group

Abstract INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous disease with varying survival rates depending mostly upon the molecular phenotype of the single leukemic clone. The most powerful predictor for the outcome of the individual patient is the cytogenetic profile at the time of diagnosis, dividing the patients into good, intermediate and adverse prognostic group. However, given that 40–60 percent of patients exhibits a normal karyotype and are assigned to an intermediate prognostic group, identification of biologic parameters, which either alone or in combination, predict disease outcome more precisely are needed. We have previously performed a gene expression profiling study (Grubach et al, Eur J. Hematol. 2008 Apr 10. [Epub ahead of print]) on a series of Polycomb, Hox and Meis genes expressed in hematopoietic cells. AIM: Based on the finding that HOXA4 could be used as a predictor for outcome in AML patients with a normal karyotype, we hypothesized that combining the gene expression of the HOXA4 gene and co-factor MEIS1 might unravel a leukemogenic impact in other cytogenetic prognostic groups (Grimwade et al. Blood. 1998 Oct 1;92(7):2322–33). In addition, given that epigenetic events might contribute to the regulation of these genes, we determined whether promoter hypermethylation of CpG islands in the promoter regions were of relevance to the expression levels of HOXA4 and MEIS1. MATERIALS & METHODS: Diagnosis samples from 248 AML patients were analyzed by RQ-PCR for expression levels of HOXA4 and MEIS1. 157 of these patients were further analyzed for promoter hypermethylation of the same genes by bisulphite treatment of DNA followed by methylation-specific melting curve analysis (MS-MCA). RESULTS: When combining the gene expression levels of HOXA4 with MEIS1 into the three main groups (low HOXA4/low MEIS1, low HOXA4/high MEIS1 and normal-high HOXA4/high MEIS1; (the latter pooled to enable statistical calculations)), clear differences in overall survival were found (Fig. 1). Thus, within the group of patients exhibiting low levels of HOXA4 transcript, those with a high expression of MEIS1 had a significantly worse outcome than those having low MEIS1 expression (p=0.025). Importantly, in a multiparameter regression analysis, the prediction was independent of the cytogenetic grouping, of mutations in NPM1 and FLT3 genes, WBC and age. Given the efficacy of demethylating therapy, we also considered the mechanism of HOXA4 and MEIS1 gene regulation. Thus, when promoter methylation of HOXA4 and MEIS1 in 157 patients was investigated, we found that 15 % of the patients had hypermethylation of the promoter region of MEIS1 and 77% of the patients showed hypermethylation of HOXA4. Importantly, a significant correlation for both of the genes between the expression level and methylation state was observed (MEIS1, p=0.001 and HOXA4, p=0.007). CONCLUSION: The altered expression levels of HOXA4 and MEIS1 in AML reflect, at least partly, an epigenetic regulation by virtue of promoter hypermethylation. The level of transcripts of HOXA4 and MEIS1 seem to contribute to the leukemogenesis in AML and can serve as independent prognostic variables regardless of their cytogenetic and molecular background. Fig. 1. Overall survival of AML patients-stratified by cytogenetics, mutations in NPM1 and FLT3, WBC and age. By combination of HOXA4 and Meis1 expression a significant better survival is linked to those with a low HOXA4/low MEIS1 compared to those with a low HOXA4/high MEIS1 expression. Fig. 1. Overall survival of AML patients-stratified by cytogenetics, mutations in NPM1 and FLT3, WBC and age. By combination of HOXA4 and Meis1 expression a significant better survival is linked to those with a low HOXA4/low MEIS1 compared to those with a low HOXA4/high MEIS1 expression.

scholarly journals Macromolecule biosynthesis: a key function of sleep

2007 ◽  
Vol 31 (3) ◽  
pp. 441-457 ◽  
Author(s):  
Miroslaw Mackiewicz ◽  
Keith R. Shockley ◽  
Micah A. Romer ◽  
Raymond J. Galante ◽  
John E. Zimmerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Sleep Deprivation ◽  
Expression Patterns ◽  
State Level ◽  
Altered Expression ◽  
Mouse Cerebral Cortex ◽  
Genes Encoding ◽  
Function Of Sleep ◽  
Cellular Components

The function(s) of sleep remains a major unanswered question in biology. We assessed changes in gene expression in the mouse cerebral cortex and hypothalamus following different durations of sleep and periods of sleep deprivation. There were significant differences in gene expression between behavioral states; we identified 3,988 genes in the cerebral cortex and 823 genes in the hypothalamus with altered expression patterns between sleep and sleep deprivation. Changes in the steady-state level of transcripts for various genes are remarkably common during sleep, as 2,090 genes in the cerebral cortex and 409 genes in the hypothalamus were defined as sleep specific and changed (increased or decreased) their expression during sleep. The largest categories of overrepresented genes increasing expression with sleep were those involved in biosynthesis and transport. In both the cerebral cortex and hypothalamus, during sleep there was upregulation of multiple genes encoding various enzymes involved in cholesterol synthesis, as well as proteins for lipid transport. There was also upregulation during sleep of genes involved in synthesis of proteins, heme, and maintenance of vesicle pools, as well as antioxidant enzymes and genes encoding proteins of energy-regulating pathways. We postulate that during sleep there is a rebuilding of multiple key cellular components in preparation for subsequent wakefulness.

scholarly journals Jonckheere–Terpstra–Kendall-based non-parametric analysis of temporal differential gene expression

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Hitoshi Iuchi ◽  
Michiaki Hamada
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Time Course ◽  
Time Series Data ◽  
Expression Patterns ◽  
Detection Methods ◽  
Series Data ◽  
Expression Levels ◽  
Over Time ◽  
Non Parametric

Abstract Time-course experiments using parallel sequencers have the potential to uncover gradual changes in cells over time that cannot be observed in a two-point comparison. An essential step in time-series data analysis is the identification of temporal differentially expressed genes (TEGs) under two conditions (e.g. control versus case). Model-based approaches, which are typical TEG detection methods, often set one parameter (e.g. degree or degree of freedom) for one dataset. This approach risks modeling of linearly increasing genes with higher-order functions, or fitting of cyclic gene expression with linear functions, thereby leading to false positives/negatives. Here, we present a Jonckheere–Terpstra–Kendall (JTK)-based non-parametric algorithm for TEG detection. Benchmarks, using simulation data, show that the JTK-based approach outperforms existing methods, especially in long time-series experiments. Additionally, application of JTK in the analysis of time-series RNA-seq data from seven tissue types, across developmental stages in mouse and rat, suggested that the wave pattern contributes to the TEG identification of JTK, not the difference in expression levels. This result suggests that JTK is a suitable algorithm when focusing on expression patterns over time rather than expression levels, such as comparisons between different species. These results show that JTK is an excellent candidate for TEG detection.

scholarly journals Exploration and validation of a novel prognostic signature based on comprehensive bioinformatics analysis in hepatocellular carcinoma

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Xiaofei Wang ◽  
Jie Qiao ◽  
Rongqi Wang
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Risk Score ◽  
Expression Profiles ◽  
Univariate Analysis ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Good Prediction ◽  
Expression Levels

Abstract The present study aimed to construct a novel signature for indicating the prognostic outcomes of hepatocellular carcinoma (HCC). Gene expression profiles were downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. The prognosis-related genes with differential expression were identified with weighted gene co-expression network analysis (WGCNA), univariate analysis, the least absolute shrinkage and selection operator (LASSO). With the stepwise regression analysis, a risk score was constructed based on the expression levels of five genes: Risk score = (−0.7736* CCNB2) + (1.0083* DYNC1LI1) + (−0.6755* KIF11) + (0.9588* SPC25) + (1.5237* KIF18A), which can be applied as a signature for predicting the prognosis of HCC patients. The prediction capacity of the risk score for overall survival was validated with both TCGA and ICGC cohorts. The 1-, 3- and 5-year ROC curves were plotted, in which the AUC was 0.842, 0.726 and 0.699 in TCGA cohort and 0.734, 0.691 and 0.700 in ICGC cohort, respectively. Moreover, the expression levels of the five genes were determined in clinical tumor and normal specimens with immunohistochemistry. The novel signature has exhibited good prediction efficacy for the overall survival of HCC patients.

scholarly journals Activation of the JAK1 / STAT1 Signaling Pathway is Associated with Prdx6 Expression Levels in Human Epididymis Epithelial Cells

2021 ◽  
Author(s):  
Jianyuan Li ◽  
Hui Shi ◽  
Xiaoyu Liu ◽  
Yanwei Wang ◽  
Haiyan Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Expression Patterns ◽  
Digital Gene Expression ◽  
Protective Role ◽  
Expression Levels ◽  
Human Epididymis ◽  
Total Antioxidant ◽  
Stat1 Signaling

Abstract I. Background: Peroxiredoxin 6 (Prdx6) is widely expressed in mammalian tissues. Our previous study demonstrated that Prdx6 was expressed in human epididymis and spermatozoa, and the protective role of Prdx6 in human spermatozoa was also reported. In this study, we demonstrate the potential role and mechanism of Prdx6 in human epididymis epithelial cells (HEECs).II. Methods and Results: Western blotting was used to measure expression levels of key proteins in the JAK / STAT signaling pathway. Digital gene expression analysis (DGE) was used to identify gene expression patterns in control HECs and in HECs after Prdx6-RNA interference (P6-RNAi). The DGE analysis identified 589 up-regulated and 314 down-regulated genes (including Prdx6) in Prdx6-RNAi (P6-RNAi) HEECs. Thirteen significantly different pathways were identified between the two groups, with the majority different expressed genes belonging to the CCL, CXCL, IL, and IFIT families. In particular, the expression levels of IL6, IL6ST, and eighteen IFN related genes were significantly increased in the condition of the down-regulated expression of Prdx6. Compared to control HEECs, the expression levels of JAK1, STAT1, phosphorylated JAK1 and STAT1 were significantly increased, while the expression levels of SOCS3 was significantly decreased in P6-RNAi HEECs. The Malondialdehyde (MDA) level and total antioxidant capacity in P6-RNAi HEECs were significantly increased and decreased compared to that of control, respectively. III. Conclusions: We speculated that knockdown of Prdx6 resulted in higher levels of ROS in HEECs, which in turn, activated the JAK1 / STAT1 signaling pathway induced by IL-6 receptor and IFN.

scholarly journals Short- and long-term impact of hyperoxia on the blood and retinal cells’ transcriptome in a mouse model of oxygen-induced retinopathy

2019 ◽  
Vol 87 (3) ◽  
pp. 485-493 ◽  
Author(s):  
Magdalena Zasada ◽  
Anna Madetko-Talowska ◽  
Cecilie Revhaug ◽  
Anne Gro W. Rognlien ◽  
Lars O. Baumbusch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mononuclear Cells ◽  
Expression Patterns ◽  
Control Group ◽  
Global Pattern ◽  
Retinal Cells ◽  
Altered Expression ◽  
Oxygen Induced Retinopathy ◽  
Blood Mononuclear Cells ◽  
Long Term Impact

Abstract Background We aimed to identify global blood and retinal gene expression patterns in murine oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity, which may allow better understanding of the pathogenesis of this severe ocular prematurity complication and identification of potential blood biomarkers. Methods A total of 120 C57BL/6J mice were randomly divided into an OIR group, in which 7-day-old pups were maintained in 75% oxygen for 5 days, or a control group. RNA was extracted from the whole-blood mononuclear cells and retinal cells on days 12, 17, and 28. Gene expression in the RNA samples was evaluated with mouse gene expression microarrays. Results There were 38, 1370 and 111 genes, the expression of which differed between the OIR and control retinas on days 12, 17, and 28, respectively. Gene expression in the blood mononuclear cells was significantly altered only on day 17. Deptor and Nol4 genes showed reduced expression both in the blood and retinal cells on day 17. Conclusion There are sustained marked changes in the global pattern of gene expression in the OIR mice retinas. An altered expression of Deptor and Nol4 genes in the blood mononuclear cells requires further investigation as they may indicate retinal neovascularization.

An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4490-4495 ◽  
Author(s):  
Lars Bullinger ◽  
Konstanze Döhner ◽  
Raphael Kranz ◽  
Christoph Stirner ◽  
Stefan Fröhling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Normal Karyotype ◽  
Mutation Status ◽  
Signature Genes ◽  
Starting Point

Abstract Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression–based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression–based measure of FLT3 pathway activation in AML.

Aberrant Expression of the MLL5, BAALC, ID1, and WT1 Genes Is Associated with Higher Induction Mortality and Poorer Overall Survival in Acute Promyelocytic Leukemia Patients Treated with ATRA and Anthracycline-Based Chemotherapy: An International Consortium On Acute Promyelocytic Leukemia Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1407-1407
Author(s):  
Antonio R Lucena-Araujo ◽  
Rafael Henriques Jacomo ◽  
Haesook T Kim ◽  
Raul A Melo ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Outcome Prediction ◽  
Promyelocytic Leukemia ◽  
Advisory Committees ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Abstract 1407 Background: Aberrant expression of MLL5, BAALC, ID1, and WT1 genes is frequently associated with inferior outcome in cytogenetically normal acute myeloid leukemia patients (Damm et al. Blood 2011; 117(17):4561–8). The expression levels of these genes vary in patients with acute promyelocytic leukemia (APL), but the clinical significance of these findings remains unclear. Objective: (1) to determine if the gene expression levels of MLL5, BAALC, ID1, and WT1 are associated with clinical outcome of APL patients treated with ATRA and anthracycline-based chemotherapy, (2) to generate an integrative score (IS) based on these potential prognostic factors and clinical parameters and (3) to use this score for outcome prediction in APL. Design and Methods: One hundred and fifty APL patients (age, 15–73y) from seven different Brazilian institutions and treated according to the IC-APL protocol were included. The treatment schedule was identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin; ATRA treatment was initiated immediately in all cases in which the diagnosis of APL was suspected based on morphology. Gene expression profile was analyzed by Real-time PCR. Integer weights for the IS were derived from Cox proportional hazard model, using overall survival (OS) as outcome parameter. Hazard ratios (HR) for OS were calculated for each variable separately (Table 1). Variables with P<0.05 in univariate analyses were included in the model. Variables considered for the model inclusion consisted in 2 clinical (WBC counts, albumin levels) and 5 molecular markers (FLT3-ITD status and gene expression levels of MLL5, BAALC, ID1, and WT1). Other candidates, such as age, platelet count, gender, ECOG performance status, PML breakpoint and FAB subtype were not significant and not included in the score. The HR were converted to integer weights according to the following: variables with HR < 1 were excluded from analyses; variables with HR 3 1 and < 1.5 were assigned a weight of 1; variables with HR 3 1.5 and < 2.5 were assigned a weight of 2; variables with HR 3 2.5 were assigned a weight of 3. The final score was the sum of these integer weights. Based on maximally selected rank statistics, the scores were grouped into 3 risk-groups: 0–5 (low-IS), 6–9 (intermediate-IS), and > 9 (high-IS). Results: The integrative weights of variables analyzed are summarized in Table 1. The IS was modeled in 137 patients (median score: 6; range, 1–17). According to PETHEMA-GIMEMA relapse risk criteria, 22%, 23% and 70% of patients assigned in the low-IS (n=46), intermediate-IS (n=57) and high-IS (n=34) groups were deemed high-risk of relapse (P<0.001). Overall, 118 (86%) patients achieved CR; the remaining 19 patients (14%) experienced early death due to hemorrhage (n=12), therapy-related infection (n=6) and differentiation syndrome (n=1). Induction mortality was significantly higher in the high-IS group (low: 2%; intermediate: 15%; high: 26%) (P=0.001). CR was achieved in the low-, intermediate-, and high-IS group in 98%, 84%, and 73% of the patients, respectively (P=0.007). With a follow-up of 24 months among survivors, patients assigned in the high-IS group had a lower 2-y OS rate (63%) compared with those in the intermediate- (80%) and low-IS groups (97%; P<0.001). Eight relapses were recorded. The IS was not predictive of relapses (P=0.351). Conclusions: Our results suggest that MLL5, BAALC, ID1, and WT1 expression levels are associated with clinical outcome and that the IS may become a useful tool for outcome prediction in APL. Disclosures: Lo-Coco: Cephalon: Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Löwenberg:Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

Mirnas and Gene Expression Profiles in CD34+ Cells Are Dependent On the Source of Progenitor Cells Employed in Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3020-3020
Author(s):  
Alicia Báez ◽  
Beatriz Martin-Antonio ◽  
Concepción Prats-Martín ◽  
Isabel Álvarez-Laderas ◽  
María Victoria Barbado ◽  
...  
Keyword(s):  
Gene Expression ◽  
Conflicts Of Interest ◽  
Reference Group ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Differentially Expressed ◽  
Expression Levels ◽  
Cd34 Cells ◽  
Different Sources

Abstract Abstract 3020 Introduction: Hematopoietic progenitors cells (HPCs) used in allogenic transplantation (allo-HSCT) may have different biological properties depending on their source of origin: mobilized peripheral blood (PB), bone marrow (BM) or umbilical cord (UC), which may be reflected in miRNAs or gene expression. The identification of different patterns of expression could have clinical implications. The aim of this study was to determine differences in miRNAs and gene expression patterns in the different sources of HPCs used in allo-HSCT. Materials and Method: CD34 + cells were isolated by immunomagnetic separation and sorting from 5 healthy donors per type of source: UC, BM and PB mobilized with G-CSF. A pool of samples from PB not mobilized was used as reference group. We analyzed the expression of 375 miRNAs using TaqMan MicroRNA Arrays Human v2.0 (Applied Biosystems), and gene expression using Whole Human Genome Oligo microarray kit 4×44K (Agilent). The expression levels of genes and miRNAs were obtained by the 2-ΔΔCTmethod. From expression data hierarchical clustering was performed using the Euclidean distance. To identify genes and miRNAs differentially expressed between the different sources of HPCs statistical Kruskal Wallis test was applied. All analysis were performed using the Multiexperiment Viewer 4.7.1. The function of the miRNAs and genes of interest was determined from the various databases available online (TAM database, Gene Ontology and TargetScan Human). Results: Forty-two miRNAs differentially expressed between the different sources were identified. As compared to BM or UC, in mobilized PB most miRNAs were overexpressed, including the miRNA family of miR515, which is characteristic of embryonic stem cells. On the other hand, 47 genes differentially expressed between the different sources were identified. Interestingly, a similar pattern of expression was observed between movilized PB and UC as compared to BM. Interestingly, 13 of these genes are targets of the miRNAs also identified in this study, which suggests that their expression might be regulated by these miRNAs. Conclusion: There are significant differences in miRNAs and gene expression levels between the different sources of HPCs Disclosures: No relevant conflicts of interest to declare.

Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 383-383
Author(s):  
Martin K. H. Maus ◽  
Craig Stephens ◽  
Stephanie H. Astrow ◽  
Peter Philipp Grimminger ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mrna Expression ◽  
Advanced Colorectal Cancer ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mutational Status ◽  
Mrna Expression Levels ◽  
Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

scholarly journals Gene expression patterns in bone following lipopolysaccharide stimulation

2014 ◽  
Vol 19 (4) ◽  
Author(s):  
Jing Yang ◽  
Nan Su ◽  
Xiaolan Du ◽  
Lin Chen
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Real Time ◽  
Real Time Pcr ◽  
Early Stage ◽  
System Development ◽  
Expression Patterns ◽  
Osteoclast Differentiation ◽  
Gene Expression Patterns ◽  
Expression Levels

AbstractBone displays suppressed osteogenesis in inflammatory diseases such as sepsis and rheumatoid arthritis. However, the underlying mechanisms have not yet been clearly explained. To identify the gene expression patterns in the bone, we performed Affymetrix Mouse Genome 430 2.0 Array with RNA isolated from mouse femurs 4 h after lipopolysaccharide (LPS) administration. The gene expressions were confirmed with real-time PCR. The serum concentration of the N-terminal propeptide of type I collagen (PINP), a bone-formation marker, was determined using ELISA. A total of 1003 transcripts were upregulated and 159 transcripts were downregulated (more than twofold upregulation or downregulation). Increased expression levels of the inflammation-related genes interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were confirmed from in the period 4 h to 72 h after LPS administration using real-time PCR. Gene ontogene analysis found four bone-related categories involved in four biological processes: system development, osteoclast differentiation, ossification and bone development. These processes involved 25 upregulated genes. In the KEGG database, we further analyzed the transforming growth factor β (TGF-β) pathway, which is strongly related to osteogenesis. The upregulated bone morphogenetic protein 2 (BMP2) and downregulated inhibitor of DNA binding 4 (Id4) expressions were further confirmed by real-time PCR after LPS stimulation. The osteoblast function was determined through examination of the expression levels of core binding factor 1 (Cbfa1) and osteocalcin (OC) in bone tissues and serum PINP from 4 h to 72 h after LPS administration. The expressions of OC and Cbfa1 decreased 6 h after administration (p < 0.05). Significantly suppressed PINP levels were observed in the later stage (from 8 h to 72 h, p < 0.05) but not in the early stage (4 h or 6 h, p > 0.05) of LPS stimulation. The results of this study suggest that LPS induces elevated expressions of skeletal system development- and osteoclast differentiation-related genes and inflammation genes at an early stage in the bone. The perturbed functions of these two groups of genes may lead to a faint change in osteogenesis at an early stage of LPS stimulation. Suppressed bone formation was found at later stages in response to LPS stimulation.

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