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Results for “Gene expression profiling”

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At least 235 records · Page 13Linked to original sources
PubMed2006

Sequential gene expression profiling in lung transplant recipients with chronic rejection.

STUDY OBJECTIVES: Chronic allograft rejection is the leading cause of morbidity and mortality for long-term survivors of lung transplantation. Previous studies have implicated only isolated genes in the development of chronic rejection and have not examined multiple pathways in an individual concurrently. Using microarray technology, we identified and compared gene expression profiling in lung transplant recipients with and without chronic rejection, and follow sequential expression of genes differentially expressed between the two groups. DESIGN: Prospective, cohort study. SETTING: Single lung transplant center. PATIENTS OR PARTICIPANTS: Eleven transplant recipients with chronic rejection were matched with 9 control transplant recipients. INTERVENTIONS: All recipients underwent surveillance bronchoscopies at predetermined times to rule out infection and/or acute rejection. Gene expression profiling was obtained from hybridizing BAL fluid cell RNA to a 96-gene microarray. MEASUREMENTS AND RESULTS: Fifteen genes were found to be significantly differentially expressed between the two patient groups, and they are involved in inflammatory, fibrotic, and apoptotic pathways. Temporal expression of the significant genes demonstrated a change in their levels at the onset of chronic rejection, with normalization to prerejection levels as rejection continued. CONCLUSIONS: We conclude that microarray technology is valuable in studying the mechanism of chronic lung rejection, and the expression of genes in multiple pathways is elevated in patients with chronic lung rejection.

Adult↗
PubMed2001

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.

Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.

Acute Disease↗
PubMed2001

Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN.

The PTEN tumor suppressor gene encodes a multifunctional phosphatase that plays an important role in inhibiting the phosphatidylinositol-3-kinase pathway and downstream functions that include activation of Akt/protein kinase B, cell survival, and cell proliferation. Enforced expression of PTEN in various cancer cell lines decreases cell proliferation through arrest of the cell cycle, accompanied in some cases by induction of apoptosis. We used cDNA microarrays containing 4009 cDNAs to examine changes in gene-expression profiles when exogenous PTEN was induced in PTEN-defective cells. The microarrays and subsequent semi-quantitative reverse transcription-PCR analysis revealed transcriptional stimulation of 99 genes and repression of 72 genes. Some of the differentially expressed genes already had been implicated in cell proliferation, differentiation, apoptosis, or cell cycle control, e.g., overexpression of PTEN-induced transactivation of cyclin-dependent inhibitor 1B (p27Kip1) and 2B (p15INK4B), members of the TNF receptor family, tumor necrosis factor-associated genes, and members of the Notch-signaling and Mad families. To our knowledge this is the first report of transactivation of those genes by PTEN. The genes differentially expressed in our experiments also included many whose correlation with cancer development had not been recognized before. Our data should contribute to a greater understanding of the broad spectrum of ways in which PTEN affects intracellular signaling pathways. Analysis of expression profiles with microarrays appears to be a powerful approach for identifying anticancer genes and/or disease-specific targets for cancer therapy.

Adenoviridae↗
PubMed2003

Systems-wide chicken DNA microarrays, gene expression profiling, and discovery of functional genes.

The goal of our current consortium project is to launch a new era--functional genomics of poultry--by providing genomic resources [expressed sequence tags (EST) and DNA microarrays] and by examining global gene expression in target tissues of chickens. DNA microarray analysis has been a fruitful strategy for the identification of functional genes in several model organisms (i.e., human, rodents, fruit fly, etc.). We have constructed and normalized five tissue-specific or multiple-tissue chicken cDNA libraries [liver, fat, breast, and leg muscle/epiphyseal growth plate, pituitary/hypothalamus/pineal, and reproductive tract (oviduct/ovary/testes)] for high-throughput DNA sequencing of EST. DNA sequence clustering was used to build contigs of overlapping sequence and to identify unique, non-redundant EST clones (unigenes), which permitted printing of systems-wide chicken DNA microarrays. One of the most promising genetic resources for gene exploration and functional gene mapping is provided by two sets of experimental lines of broiler-type chickens developed at INRA, France, by divergent selection for extremes in growth traits (fast-growing versus slow-growing; fatness versus leanness at a similar growth rate). We are using DNA microarrays for global gene expression profiling to identify candidate genes and to map growth, metabolic, and regulatory pathways that control important production traits. Candidate genes will be used for functional gene mapping and QTL analysis of F2 progeny from intercrosses made between divergent genetic lines (fat x lean lines; fast-growing x slow-growing lines). Using our first chicken liver microarray, we have already identified several interesting differentially expressed genes in commercial broilers and in divergently selected broiler lines. Many of these candidate genes are involved in the lipogenic pathway and are controlled in part by the thyrotropic axis. Thus, genome-wide transcriptional profiling is a powerful tool used to visualize the cascade of genetic circuits that govern complex biological responses. Global gene expression profiling and QTL scans should enable us to functionally map the genetic pathways that control growth, development, and metabolism of chickens. This emerging technology will have broad applications for poultry breeding programs (i.e., use of molecular markers) and for future production systems (i.e., the health and welfare of birds and the quality of poultry products).

Animal Husbandry↗
PubMed2006

Algorithm to find gene expression profiles of deregulation and identify families of disease-altered genes.

MOTIVATION: Alteration of gene expression often results in up- or down-regulated genes and the most common analysis strategies look for such differentially expressed genes. However, molecular disease mechanisms typically constitute abnormalities in the regulation of genes producing strong alterations in the expression levels. The search for such deregulation states in the genomic expression profiles will help to identify disease-altered genes better. RESULTS: We have developed an algorithm that searches for the genes which present a significant alteration in the variability of their expression profiles, by comparing an altered state with a control state. The algorithm provides groups of genes and assigns a statistical measure of significance to each group of genes selected. The method also includes a prefilter tool to select genes with a threshold of differential expression that can be set by the user ad casum. The method is evaluated using an experimental set of microarrays of human control and cancer samples from patients with acute promyelocytic leukemia.

Algorithms↗
PubMed2005

Gene expression profiling in conjunction with physiological rescues of IKKalpha-null cells with wild type or mutant IKKalpha reveals distinct classes of IKKalpha/NF-kappaB-dependent genes.

Cellular responses to stress-like stimuli require the IkappaB kinase (IKK) signalsome (IKKalpha, IKKbeta, and NEMO/IKKgamma) to activate NF-kappaB-dependent genes. IKKbeta and NEMO/IKKgamma are required to release NF-kappaB p65/p50 heterodimers from IkappaBalpha, resulting in their nuclear migration and sequence-specific DNA binding; but IKKalpha was found to be dispensable for this initial phase of canonical NF-kappaB activation. Nevertheless, IKKalpha-/- mouse embryonic fibroblasts (MEFs) fail to express NF-kappaB targets in response to proinflammatory stimuli, uncovering a nuclear role for IKKalpha in NF-kappaB activation. However, it remains unknown whether the global defect in NF-kappaB-dependent gene expression of IKKalpha-/- cells is caused by the absence of IKKalpha kinase activity. We show by gene expression profiling that rescue of near physiological levels of wild type IKKalpha in IKKalpha-/- MEFs globally restores expression of their canonical NF-kappaB target genes. To prove that the kinase activity of IKKalpha was required on a genomic scale, the same physiological rescue was performed with a kinase-dead, ATP binding domain IKKalpha mutant (IKKalpha(K44M)). Remarkably, the IKKalpha(K44M) protein rescued approximately 28% of these genes, albeit in a largely stimulus-independent manner with the notable exception of several genes that also acquired tumor necrosis factor-alpha responsiveness. Thus the IKKalpha-containing signalsome unexpectedly functions in the presence and absence of extracellular signals in both kinase-dependent and -independent modes to differentially modulate the expression of five distinct classes of IKKalpha/NF-kappaB-dependent genes.

Animals↗
PubMed2002

Gene expression profiling of human GV oocytes: an analysis of a profile obtained by Serial Analysis of Gene Expression (SAGE).

A gene expression profile of the human GV oocyte has recently been established by Serial Analysis of Gene Expression (SAGE). A significant number of the genes identified in this profile had not previously been associated with mammalian oocytes. We sought to confirm gene matches by RT-PCR amplification of candidate transcripts using mouse eggs. Attention focused on receptors, proteins involved in apoptosis, and cytoskeletal proteins. Two receptors found in the human catalogue, CCR6 and PAR3, were not found in mouse eggs, whereas myosin light chain, LLGL, beta-actin, 5HT receptor, bad, bak, DFF45, and Caspase homologue (cash) were. Individual SAGEtags can match more than one gene and, in some cases, more than ten. Examination of transcript sequences that generate multiple gene assignments identified a common denominator of short interspersed elements or Alu sequences. For reasons which are, as yet, unclear, the human GV oocyte SAGE catalogue contains relatively high abundances of SAGEtags in Alu sequences. This may reflect normal expression of Alu-containing genes in eggs or upregulated expression of Alu elements following stress. The degeneracy of gene matches in SAGE generated by Alu sequences makes independent confirmation of candidate genes essential.

3' Untranslated Regions↗
PubMed2002

Gene expression profiling of lymphoid malignancies.

Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-kappa B signaling pathway is a new molecular therapeutic target in DLBCL.

DNA-Binding Proteins↗
PubMed2003

Identification of molecular subtypes of glioblastoma by gene expression profiling.

Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFR-) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13-15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.

Astrocytes↗
PubMed2004

Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection: identification of genes associated with progression and metastasis.

Breast carcinoma is a complex disease characterized by accumulation of multiple genetic alterations, and the understanding of the molecular basis of mammary tumorigenesis is still incomplete. In this study we analyzed gene-expression profiles of 81 surgical specimens of 12 ductal carcinoma in situ (DCIS) and 69 invasive ductal carcinoma (IDC). After applying laser-microbeam micro-dissection to all samples we achieved 98-99% pure populations of breast cancer cells, and of normal breast epithelial cells used as controls. A cDNA-microarray analysis of 23,040 genes in these samples and a subsequent unsupervised hierarchical clustering distinguished two tumor groups, mainly in terms of estrogen-receptor (ER) status. We then undertook a supervised analysis and identified 325 genes that were commonly either up- or down-regulated in both pathologically discrete stages (DCIS and IDC), indicating that these genes might play important roles in malignant transformation of breast ductal cells. In addition, we searched invasion-associated gene candidates whose expression was altered in IDC, but not in DCIS, and identified 24 up-regulated genes and 41 down-regulated genes. Furthermore, we identified 34 genes that were expressed differently in tumors from patients with lymph node metastasis as opposed to no metastasis. On that basis we developed a scoring system that correlated well with the metastatic status. Tumors from all of the 37 test patients with lymph-node metastasis yielded positive scores by our definition, whereas 38 of the 40 tumors (95%) without lymph node metastasis had negative scores. Our data should provide useful information for identifying predictive markers for invasion or metastasis, and suggest potential target molecules for treatment of breast cancers.

Adult↗
PubMed2003

Diffuse large B-cell lymphoma: insights gained from gene expression profiling.

Analysis of global gene expression with DNA microarrays has great potential to improve the understanding of tumorigenesis advance tumor diagnosis and classification, and affect cancer treatment. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. However, we now realize that the disease is extremely heterogeneous. This review summarizes the progress in understanding DLBCL that has been made as a result of the application of gene expression profiling.

Gene Expression Profiling↗
PubMed2003

Analysis of gene expression profiles of gastric normal and cancer tissues by SAGE.

In an attempt to understand the molecular bases of gastric cancer progression, we have analyzed the differentially expressed genes in gastric cancer by SAGE. Four SAGE cDNA tag libraries were constructed from two sets of gastric cancer and normal tissues and 241,127 tags were obtained. By comparing the tags from cancer and normal tissues, 414 differentially expressed tags, representing 383 genes, were identified in cancer tissues (p </= 0.01). Of the 414 tags, 50 tags were previously unidentified and potentially novel genes. Although each gastric cancer tissue revealed more than 200 differentially expressed genes compared to the respective normal tissue, the number of genes with consistent regulation patterns in both cancer tissues was 51: 12 up-regulated and 39 down-regulated genes. The genes that showed consistent regulation patterns included well-known genes such as Trefoil factor 3, RegIV, gastric intrinsic factor, and lactotransferrin as well as a few novel candidates. Interestingly, the expression of several genes, such as osteoglycin, prostate stem cell antigen, and histone deacetylase 3, was variable in the two normal tissues but similar in the cancer tissues. The expression profiles of these genes in normal tissues, possibly due to genetic background, could greatly affect individual sensitivity to cancer development and/or progression. The genes identified in this study will provide useful target genes for diagnosis and molecular treatment of gastric cancer.

Adenocarcinoma↗
PubMed2005

New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling.

To gain more insight into initiation and regulation of T cell receptor (TCR) gene rearrangement during human T cell development, we analyzed TCR gene rearrangements by quantitative PCR analysis in nine consecutive T cell developmental stages, including CD34+ lin- cord blood cells as a reference. The same stages were used for gene expression profiling using DNA microarrays. We show that TCR loci rearrange in a highly ordered way (TCRD-TCRG-TCRB-TCRA) and that the initiating Ddelta2-Ddelta3 rearrangement occurs at the most immature CD34+CD38-CD1a- stage. TCRB rearrangement starts at the CD34+CD38+CD1a- stage and complete in-frame TCRB rearrangements were first detected in the immature single positive stage. TCRB rearrangement data together with the PTCRA (pTalpha) expression pattern show that human TCRbeta-selection occurs at the CD34+CD38+CD1a+ stage. By combining the TCR rearrangement data with gene expression data, we identified candidate factors for the initiation/regulation of TCR recombination. Our data demonstrate that a number of key events occur earlier than assumed previously; therefore, human T cell development is much more similar to murine T cell development than reported before.

Animals↗
PubMed2001

Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes.

To elucidate the biological dysregulation underlying two forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), we examined global gene expression profiles of inflamed colonic tissue using DNA microarrays. Our results identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3, IGLL2 and CD74, inflammation-related lipocalins HNL and NGAL, and proliferation-related GRO genes were over-expressed in UC. Certain cancer-related genes such as DD96, DRAL and MXI1 were differentially expressed only in UC. Other genes over-expressed in both UC and CD included the REG gene family and the calcium-binding S100 protein genes S100A9 and S100P. The natural antimicrobial defensin DEFA5 and DEFA6 genes were particularly over-expressed in CD. Overall, significant differences in the expression profiles of 170 genes identified UC and CD as distinct molecular entities. The genomic map locations of the dysregulated genes may identify novel candidates for UC and CD genetic susceptibility.

Adult↗
PubMed2006

Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification.

BACKGROUND: The aggressiveness of metastatic neuroblastomas that lack MYCN gene amplification varies with age--they are least aggressive when diagnosed in patients younger than 12 months and most aggressive when diagnosed in patients older than 24 months. However, age at diagnosis is not always associated with patient survival. We examined whether molecular classification of metastatic neuroblastomas without MYCN gene amplification at diagnosis using gene expression profiling could improve the prediction of risk of disease progression. METHODS: We used Affymetrix microarrays to determine the gene expression profiles of 102 untreated primary neuroblastomas without MYCN gene amplification obtained from children whose ages at diagnosis ranged from 0.1 to 151 months. A supervised method using diagonal linear discriminant analysis was devised to build a multigene model for predicting risk of disease progression. The accuracy of the model was evaluated using nested cross-validations, permutation analyses, and gene expression data from 15 additional tumors obtained at disease progression. RESULTS: An expression profile model using 55 genes defined a tumor signature that distinguished two groups of patients from among those older than 12 months at diagnosis and clinically classified as having high-risk disease, those with a progression-free survival (PFS) rate of 16% (95% confidence interval [CI] = 8% to 28%), and those with a PFS rate of 79% (95% CI = 57% to 91%) (P<.01). These tumor signatures also identified two groups of patients with PFS of 15% (95% CI = 7% to 27%) and 69% (95% CI = 40% to 86%) (P<.01) from among patients who were older than 18 months at diagnosis. The gene expression signature of untreated molecular high-risk tumors was also present in progressively growing tumors. CONCLUSION: Gene expression signatures of tumors obtained at diagnosis from patients with clinically indistinguishable high-risk, metastatic neuroblastomas identify subgroups with different outcomes. Accurate identification of these subgroups with gene expression profiles may facilitate development, implementation, and analysis of clinical trials aimed at improving outcome.

Adolescent↗
PubMed2005

Gene expression profiling of muscle tissue in Brahman steers during nutritional restriction.

Expression profiling using microarrays allows for the detailed characterization of the gene networks that regulate an animal's response to environmental stresses. During nutritional restriction, processes such as protein turnover, connective tissue remodeling, and muscle atrophy take place in the skeletal muscle of the animal. These processes and their regulation are of interest in the context of managing livestock for optimal production efficiency and product quality. Here we expand on recent research applying complementary DNA (cDNA) microarray technology to the study of the effect of nutritional restriction on bovine skeletal muscle. Using a custom cDNA microarray of 9,274 probes from cattle muscle and s.c. fat libraries, we examined the differential gene expression profile of the LM from 10 Brahman steers under three different dietary treatments. The statistical approach was based on mixed-model ANOVA and model-based clustering of the BLUP solutions for the gene x diet interaction effect. From the results, we defined a transcript profile of 156 differentially expressed array elements between the weight loss and weight gain diet substrates. After sequence and annotation analyses, the 57 upregulated elements represented 29 unique genes, and the 99 downregulated elements represented 28 unique genes. Most of these co-regulated genes cluster into groups with distinct biological function related to protein turnover and cytoskeletal metabolism and contribute to our mechanistic understanding of the processes associated with remodeling of muscle tissue in response to nutritional stress.

Analysis of Variance↗
PubMed2003

Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas.

Endometrial carcinoma (EC) comprises at least two types of cancer: endometrioid carcinomas (EECs) are estrogen-related tumors, which are frequently euploid and have a good prognosis. Nonendometrioid carcinomas (NEECs; serous and clear cell forms) are not estrogen related, are frequently aneuploid, and are clinically aggressive. We used cDNA microarrays containing 6386 different genes to analyze gene expression profiles in 24 EECs and 11 NEECs to identify differentially expressed genes that could help us to understand differences in the biology and clinical outcome between histotypes. After supervised analysis of the microarray data, there was at least a 2-fold difference in expression between EEC and NEEC in 66 genes. The 31 genes up-regulated in EECs included genes known to be hormonally regulated during the menstrual cycle and to be important in endometrial homeostasis, such as MGB2, LTF, END1, and MMP11, supporting the notion that EEC is a hormone-related neoplasm. Conversely, of the 35 genes overexpressed in NEECs, three genes, STK15, BUB1, and CCNB2, are involved in the regulation of the mitotic spindle checkpoint. Because STK15 amplification/overexpression is associated with aneuploidy and an aggressive phenotype in other human tumors, we used fluorescence in situ hybridization to investigate whether STK15 amplification occurred in ECs. We found that STK15 was amplified in 55.5% of NEECs but not in any EECs (P <or= 0.001). We confirmed this result in an independent series of ECs included in a tissue microarray in which breast and ovarian cancer samples showed an incidence of STK15 amplification of 15 and 18%, respectively (P <or= 0.001). This study demonstrated the usefulness of cDNA microarray technology for identifying differences in gene expression patterns between histological types of EC and implies that alteration of the mitotic checkpoint is a major mechanism of carcinogenesis in NEECs.

Aurora Kinase A↗
PubMed2005

Gene expression profiling of the irinotecan pathway in colorectal cancer.

The exact mechanism responsible for large variation of response to chemotherapy remains unclear. This study profiled the gene expression for the entire irinotecan pathway to provide insights into individualized cancer therapy. The RNA expressions of 24 irinotecan pathway genes were measured in paired tumor and normal tissues from 52 patients with Dukes' C colorectal cancer using a real-time quantitative reverse transcription-PCR assay. The relative expression levels across the 24 pathway genes varied considerably, with a 441-fold range from highest to lowest expression levels for the tumor tissues and a 934-fold range for the normal tissues. Interpatient variability was also quite large, with a 33.6 median fold change in the tumor tissue genes and a 30.1 median fold change in the normal tissue genes. Six of the 24 irinotecan pathway genes had dramatically lower expression levels in the tumor samples than did the genes in the normal tissues (median range, 1.28-4.39 folds; P = 0.001-0.029). Eight genes had significantly higher levels (median range, 1.35-2.42 folds; P = 0.001-0.011). Using hierarchical clustering, three gene clusters and three patient groups were observed with high similarity indices by the RNA expressions in colorectal tumors. The three patient groups had no unique clinical pathologic features but could be differentiated by the statistically significant differences in RNA expression level of seven genes. Our study indicates that gene expression profiling could be valuable for predicting tumor response to chemotherapy and for tailoring therapy to individual cancer patients.

Antineoplastic Agents, Phytogenic↗