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At least 343 records · Page 19Linked to original sources
PubMed2005

Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation.

The difficulty to dissect a complex phenotype of established malignant cells to several critical transcriptional programs greatly impedes our understanding of the malignant transformation. The genetic elements required to transform some primary human cells to a tumorigenic state were described in several recent studies. We took the advantage of the global genomic profiling approach and tried to go one step further in the dissection of the transformation network. We sought to identify the genetic signatures and key target genes, which underlie the genetic alterations in p53, Ras, INK4A locus, and telomerase, introduced in a stepwise manner into primary human fibroblasts. Here, we show that these are the minimally required genetic alterations for sarcomagenesis in vivo. A genome-wide expression profiling identified distinct genetic signatures corresponding to the genetic alterations listed above. Most importantly, unique transformation hallmarks, such as differentiation block, aberrant mitotic progression, increased angiogenesis, and invasiveness, were identified and coupled with genetic signatures assigned for the genetic alterations in the p53, INK4A locus, and H-Ras, respectively. Furthermore, a transcriptional program that defines the cellular response to p53 inactivation was an excellent predictor of metastasis development and bad prognosis in breast cancer patients. Deciphering these transformation fingerprints, which are affected by the most common oncogenic mutations, provides considerable insight into regulatory circuits controlling malignant transformation and will hopefully open new avenues for rational therapeutic decisions.

Cell Differentiation↗
PubMed2006

Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes.

Autism is a complex neurodevelopmental disorder having both genetic and epigenetic etiological elements. Isodicentric chromosome 15 (Idic15), characterized by duplications of the multi-disorder critical region of 15q11-q14, is a relatively common cytogenetic event. When the duplication involves maternally derived content, this abnormality is strongly correlated with autism disorder. However, the mechanistic links between Idic15 and autism are ill-defined. To gain insight into the potential role of these duplications, we performed a comprehensive, genomics-based characterization of an in vitro model system consisting of lymphoblast cell lines derived from individuals with both autism and Idic15. Array-based comparative genomic hybridization using commercial single nucleotide polymorphism arrays was conducted and found to be capable of sub-classifying Idic15 samples by virtue of the lengths of the duplicated chromosomal region. In further analysis, whole-genome expression profiling revealed that 112 transcripts were significantly dysregulated in samples harboring duplications. Paramount among changing genes was ubiquitin protein ligase E3A (UBE3A; 15q11-q13), which was found to be nearly 1.5-2.0-fold up-regulated in duplicated samples at both the RNA and protein levels. Other key findings from gene expression analysis included two down-regulated genes, APP and SUMO1, with well-characterized roles in the process of apoptosis. We further demonstrate in this lymphoblast model that the gene-dosage directed increases in UBE3A levels can lead to dysregulation of the process of ubiquitination in response to genotoxic insult. This study provides insight into the direct and indirect effects of copy number gains in chromosome 15 and provides a framework for the study of these effects in neuronal systems.

Cell Line, Transformed↗
PubMed1983

A survey of electropherotype relationships of bluetongue virus isolates from the western United States.

The genome profiles of 200 field isolates of bluetongue virus were obtained by extracting the double-stranded RNA genome from each isolate and separating the ten genome segments by polyacrylamide gel electrophoresis. These virus isolates, consisting of representatives of the four bluetongue virus serotypes existing in the U.S.A., were obtained during an epidemiological study commencing in 1979 in four western states of the United States. Analysis of the migration patterns of the ten double-stranded RNA genome segments revealed distinct variations of electrophoretic profiles of many isolates. These variations are discussed in relation to the year and geographical region in which the isolate was made, the species of animal from which the virus was obtained and the electropherotype relationships of the four bluetongue virus serotypes existing in the U.S.A.

Animals↗
PubMed1997

A t-statistic for objective interpretation of comparative genomic hybridization (CGH) profiles.

An objective method for interpreting comparative genomic hybridization (CGH) is described and compared with current methods of interpretation. The method is based on a two-sample t-statistic in which composite test:reference and reference:reference CGH profiles are compared at each point along the genome to detect regions of significant differences. Composite profiles are created by combining CGH profiles measured from several metaphase chromosomes for each type of chromosome in the normal human karyotype. Composites for both test:reference and reference:reference CGH analyses are used to generate mean CGH profiles and information about the variance therein. The utility of the method is demonstrated through analysis of aneusomies and partial gain and loss of DNA sequence in a myeloid leukemia specimen. Banding analyses of this specimen indicated inv (3)(q21q26), del (5)(q2?q35), -7, +8 and add (17)(p11.2). The t-statistic analyses of CGH data indicated rev ish enh (8) and rev ish dim (5q31.1q33.1,7q11.23qter). The undetected gain on 17p was small and confined to a single band (17p11.2). Thus, the t-statistic is an objective and effective method for defining significant differences between test and reference CGH profiles.

Humans↗
PubMed2004

Genome wide expression profiling of angiogenic signaling and the Heisenberg uncertainty principle.

Genome wide DNA expression profiling coupled with antibody array experiments using endostatin to probe the angiogenic signaling network in human endothelial cells were performed. The results reveal constraints on the measuring process that are of a similar kind as those implied by the uncertainty principle of quantum mechanics as described by Werner Heisenberg. We describe this analogy and argue for its heuristic utility in the conceptualization of angiogenesis as an important step in tumor formation.

Angiogenesis Inhibitors↗
PubMed2005

Microarray expression profiling resources for plant genomics.

Large volumes of genomic data have been generated for several plant species over the past decade, including structural sequence data and functional annotation at the genome level. Various technologies such as expressed sequence tags (ESTs), massively parallel signature sequencing (MPSS) and microarrays have been used to study gene expression and to provide functional data for many genes simultaneously. This review focuses on recent advances in the application of microarrays in plant genomic research and in gene expression databases available for plants. Large sets of Arabidopsis microarray data are publicly available. Recently developed array platforms are currently being used to generate genome-wide expression profiles for several crop species. Coupled to these platforms are public databases that provide access to these large-scale expression data, which can be used to aid the functional discovery of gene function.

Arabidopsis↗
PubMed2003

Genome-scale functional profiling of the mammalian AP-1 signaling pathway.

Large-scale functional genomics approaches are fundamental to the characterization of mammalian transcriptomes annotated by genome sequencing projects. Although current high-throughput strategies systematically survey either transcriptional or biochemical networks, analogous genome-scale investigations that analyze gene function in mammalian cells have yet to be fully realized. Through transient overexpression analysis, we describe the parallel interrogation of approximately 20,000 sequence annotated genes in cancer-related signaling pathways. For experimental validation of these genome data, we apply an integrative strategy to characterize previously unreported effectors of activator protein-1 (AP-1) mediated growth and mitogenic response pathways. These studies identify the ADP-ribosylation factor GTPase-activating protein Centaurin alpha1 and a Tudor domain-containing hypothetical protein as putative AP-1 regulatory oncogenes. These results provide insight into the composition of the AP-1 signaling machinery and validate this approach as a tractable platform for genome-wide functional analysis.

Animals↗
PubMed2005

When will more useful predictive factors be ready for use?

Adjuvant chemotherapy is widely used, but its performance is not optimal. Two subgroups of patients do not get any benefit from adjuvant chemotherapy: the first one comprises patients who are already cured by locoregional treatment alone and the second one patients who do not profit from adjuvant chemotherapy because of resistance to the regimens employed. To improve the cost/benefit of this treatment strategy, we have two means: one is to improve the sensitivity of prognostic factors to be able to select a specific group with a good signature that does not need adjuvant treatment; the second is to identify predictive factors that may help us to select the optimal therapeutic strategy or the optimal regimen or drug for individual patients. New technologies of microarray revealed several genetic profiles. A large randomized trial (Microarray In Node-negative Disease may Avoid ChemoTherapy, MINDACT) will compare the information obtained with the genomic profiling and the classical clinico-pathologic index (St Gallen); the objective is to allow women not to be treated with adjuvant chemotherapy if their genomic signature is good. Another trial (EORTC 10994) is conducted in order to show that in cases of p53 mutated tumors, neoadjuvant chemotherapy with docetaxel is more efficient than an anthracycline-containing regimen. A supplementary study will evaluate gene profile predicting for p53 status. So, new genomic prognostic factors are still in development and seem very promising for optimizing the indications for adjuvant chemotherapy.

Breast Neoplasms↗
PubMed2005

A wheat intervarietal genetic linkage map based on microsatellite and target region amplified polymorphism markers and its utility for detecting quantitative trait loci.

Efficient user-friendly methods for mapping plant genomes are highly desirable for the identification of quantitative trait loci (QTLs), genotypic profiling, genomic studies, and marker-assisted selection. SSR (microsatellite) markers are user-friendly and efficient in detecting polymorphism, but they detect few loci. Target region amplification polymorphism (TRAP) is a relatively new PCR-based technique that detects a large number of loci from a single reaction without extensive pre-PCR processing of samples. In the investigation reported here, we used both SSRs and TRAPs to generate over 700 markers for the construction of a genetic linkage map in a hard red spring wheat intervarietal recombinant inbred population. A framework map consisting of 352 markers accounted for 3,045 cM with an average density of one marker per 8.7 cM. On average, SSRs detected 1.9 polymorphic loci per reaction, while TRAPs detected 24. Both marker systems were suitable for assigning linkage groups to chromosomes using wheat aneuploid stocks. We demonstrated the utility of the maps by identifying major QTLs for days to heading and reduced plant height on chromosomes 5A and 4B, respectively. Our results indicate that TRAPs are highly efficient for genetic mapping in wheat. The maps developed will be useful for the identification of quality and disease resistance QTLs that segregate in this population.

Chromosome Mapping↗
PubMed2005

Optimal design and analysis of genetic studies on gene expression.

Whole-genome profiling of gene expression in a segregating population has the potential to identify the regulatory consequences of natural allelic variation. Costs of such studies are high and require that resources--microarrays and population--are used as efficiently as possible. We show that current studies can be improved significantly by a new design for two-color microarrays. Our "distant pair design" profiles twice as many individuals as there are arrays, cohybridizes individuals with dissimilar genomes, gives more weight to known regulatory loci if wished, and therewith maximizes the power for decomposing expression variation into regulatory factors. It can also exploit a large population (larger than twice the number of available microarrays) as a useful resource to select the most dissimilar pairs of individuals from. Our approach identifies more regulatory factors than alternative strategies do in computer simulations for realistic genome sizes, and similar promising results are obtained in an application on Arabidopsis thaliana. Our results will aid the design and analysis of future studies on gene expression and will help to shed more light on gene regulatory networks.

Arabidopsis↗
PubMed2026

Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.

Cholangiocarcinomas (CCAs) are aggressive biliary tumors that can develop within the intrahepatic (iCCA) or perihilar and distal bile ducts. The prognosis of patients with iCCA is poor due to its relative resistance to chemotherapy. Comprehensive genomic profiling of CCA biopsies by next-generation sequencing has revealed a rich landscape of genomic alterations, including fibroblast growth factor receptor (FGFR) gene fusions and rearrangements that are constitutively active and oncogenic. Several FGFR inhibitors (FGFRis) targeting these FGFR genomic alterations have been developed as potential treatments for iCCA, each of which are highly potent but differ in structure, mechanism of inhibition (ie, adenosine triphosphate-competitive reversible v covalent/irreversible v allosteric), pharmacologic/pharmacodynamic profiles, and selectivity for the four FGFR isoforms. Because of these differences, and due to resistance mutations acquired during FGFRi treatment, determining the optimal sequencing of FGFRis for the treatment of CCA remains contentious and is the subject of ongoing debate. To address this question, this review conducted an analysis of the literature on the FGFRi currently approved or in development, focusing on their distinct mechanisms of action and FGFR selectivity. Publicly available data from case reports on FGFRi sequencing in second and later lines of treatment were compiled from a PubMed search of published congress abstracts and articles. The results support a hypothesis that strategic sequencing of reversible followed by irreversible FGFRi may potentially prolong the duration of treatment benefit from FGFR inhibition compared with nonsequenced treatments. A hypothetical treatment-sequencing algorithm for reversible and irreversible FGFRi is discussed.

Humans↗
PubMed2003

Comparing bacterial genomes through conservation profiles.

We constructed two-dimensional representations of profiles of gene conservation across different genomes using the genome of Escherichia coli as a model. These profiles permit both the visualization at the genome level of different traits in the organism studied and, at the same time, reveal features related to the genomes analyzed (such as defective genomes or genomes that lack a particular system). Conserved genes are not uniformly distributed along the E. coli genome but tend to cluster together. The study of gene distribution patterns across genomes is important for the understanding of how sets of genes seem to be dependent on each other, probably having some functional link. This provides additional evidence that can be used for the elucidation of the function of unannotated genes. Clustering these patterns produces families of genes which can be arranged in a hierarchy of closeness. In this way, functions can be defined at different levels of generality depending on the level of the hierarchy that is studied. The combined study of conservation and phenotypic traits opens up the possibility of defining phenotype/genotype associations, and ultimately inferring the gene or genes responsible for a particular trait.

Chromosome Mapping↗
PubMed2026

Accelerating Lung Cancer Management Through Previsit Liquid Biopsy: Results From the LUNG-FAST Pilot Study.

BACKGROUND: Timely molecular profiling is essential for treatment selection in non-small cell lung cancer (NSCLC), yet delays in biomarker testing remain common. We evaluated the feasibility and early clinical impact of a nurse navigator-driven workflow to initiate liquid biopsy before the initial oncology visit. METHODS: LUNG-FAST (Liquid Biopsy for Urgent Neoplastic Genomic Profiling Focused Accelerated Stratification and Testing) was a 4-month prospective pilot at a tertiary cancer center. Intake nurse navigators identified eligible patients with suspected or newly diagnosed lung cancer and facilitated previsit liquid biopsy ordering. Feasibility, turnaround times, genomic findings, and early clinical outcomes were assessed. RESULTS: Among 64 patients, intake nurse navigators identified 94% (60/64) of eligible cases. Liquid biopsy was ordered in 58 patients, with 62% (36/58) placed before the initial oncology visit. Median turnaround time from blood draw to results was 8.5 days for commercial testing and 12.5 days for institutional testing. FDA-actionable genomic alterations were identified in 34% (22/64) of patients, while an additional 11% (7/64) harbored clinically relevant, non-FDA-actionable alterations. Overall, FDA-actionable or clinically relevant alterations were identified in 45% (29/64), with 22% detected by liquid biopsy and an additional 23% by tissue-only profiling. Median time from new patient visit to systemic therapy was 26 days. CONCLUSIONS: A nurse navigator-driven workflow enabling previsit liquid biopsy is feasible and identifies actionable genomic alterations in a substantial proportion of patients with lung cancer. Plasma and tissue profiling are complementary, and earlier plasma-based testing may expedite treatment decision-making while highlighting opportunities to optimize biomarker testing workflows.

Humans↗
PubMed2000

Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles.

Genome-wide transcript profiling was used to monitor signal transduction during yeast pheromone response. Genetic manipulations allowed analysis of changes in gene expression underlying pheromone signaling, cell cycle control, and polarized morphogenesis. A two-dimensional hierarchical clustered matrix, covering 383 of the most highly regulated genes, was constructed from 46 diverse experimental conditions. Diagnostic subsets of coexpressed genes reflected signaling activity, cross talk, and overlap of multiple mitogen-activated protein kinase (MAPK) pathways. Analysis of the profiles specified by two different MAPKs-Fus3p and Kss1p-revealed functional overlap of the filamentous growth and mating responses. Global transcript analysis reflects biological responses associated with the activation and perturbation of signal transduction pathways.

Cell Cycle Proteins↗
PubMed2004

Cross-sectional analysis of clinical and environmental isolates of Pseudomonas aeruginosa: biofilm formation, virulence, and genome diversity.

Chronic lung infections with Pseudomonas aeruginosa biofilms are associated with refractory and fatal pneumonia in cystic fibrosis (CF). In this study, a group of genomically diverse P. aeruginosa isolates were compared with the reference strain PAO1 to assess the roles of motility, twitching, growth rate, and overproduction of a capsular polysaccharide (alginate) in biofilm formation. In an in vitro biofilm assay system, P. aeruginosa displayed strain-specific biofilm formation that was not solely dependent on these parameters. Compared with non-CF isolates, CF isolates expressed two opposing growth modes: reduced planktonic growth versus efficient biofilm formation. Planktonic cells of CF isolates showed elevated sensitivity to hydrogen peroxide, a reactive oxygen intermediate, and decreased lung colonization in an aerosol infection mouse model. Despite having identical genomic profiles, CF sequential isolates produced different amounts of biofilm. While P. aeruginosa isolates exhibited genomic diversity, the genome size of these isolates was estimated to be 0.4 to 19% (27 to 1,184 kb) larger than that of PAO1. To identify these extra genetic materials, random amplification of polymorphic DNA was coupled with PAO1-subtractive hybridization. Three loci were found within the genomes of two CF isolates encoding one novel homolog involved in retaining a Shigella virulence plasmid (mvpTA) and two divergent genes that function in removing negative supercoiling (topA) and biosynthesis of pyoverdine (PA2402). Together, P. aeruginosa biodiversity could provide one cause for the variation of morbidity and mortality in CF. P. aeruginosa may possess undefined biofilm adhesins that are important to the development of an antibiofilm therapeutic target.

Animals↗
PubMed2006

Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays.

Recurrent genomic aberrations are important prognostic parameters in chronic lymphocytic leukemia (CLL). High-resolution 10k and 50k Affymetrix SNP arrays were evaluated as a diagnostic tool for CLL and revealed chromosomal imbalances in 65.6% and 81.5% of 70 consecutive cases, respectively. Among the prognostically important aberrations, the del13q14 was present in 36 (51.4%), trisomy 12 in 9 (12.8%), del11q22 in 9 (12.8%), and del17p13 in 4 cases (5.7%). A prominent clustering of breakpoints on both sides of the MIRN15A/MIRN16-1 genes indicated the presence of recombination hot spots in the 13q14 region. Patients with a monoallelic del13q14 had slower lymphocyte growth kinetics (P=.002) than patients with biallelic deletions. In 4 CLL cases with unmutated VH genes, a common minimal 3.5-Mb gain of 2p16 spanning the REL and BCL11A oncogenes was identified, implicating these genes in the pathogenesis of CLL. Twenty-four large (>10 Mb) copy-neutral regions with loss of heterozygosity were identified in 14 cases. These regions with loss of heterozygosity are not detectable by alternative methods and may harbor novel imprinted genes or loss-of-function alleles that may be important for the pathogenesis of CLL. Genomic profiling with SNP arrays is a convenient and efficient screening method for simultaneous genome-wide detection of chromosomal aberrations.

Adult↗
PubMed2026

Comparative genomic epidemiology of food- and patient-derived diarrheagenic Escherichia coli from sentinel surveillance in Southeast China.

Diarrheagenic Escherichia coli (DEC) remains an important foodborne pathogen, yet long-term comparative genomic surveillance data jointly characterizing food-derived and patient-derived isolates remain limited. This surveillance-based comparative study integrated antimicrobial susceptibility testing and whole-genome sequencing to characterize diarrheagenic Escherichia coli isolates recovered from food and patient sources in Lishui, Southeast China, during 2018-2025, with emphasis on occurrence, resistance profiles, genomic backgrounds, and plasmid replicon-associated features. Antimicrobial susceptibility testing was performed for 258 selected isolates, and whole-genome sequencing was conducted for a curated analytical subset of 204 isolates. The sequenced subset was used for diversity-oriented comparative genomic analysis rather than for unbiased prevalence estimation of the entire DEC collection. EAEC predominated in both sources, although food-associated occurrence was heterogeneous across categories, with the highest recovery rate observed in raw meat. Patient-derived isolates showed a broader overall resistance burden, whereas food-derived isolates retained substantial resistance to tetracycline, chloramphenicol, and florfenicol. Phylogenetic analysis showed partial overlap in genomic backgrounds between food-derived and patient-derived isolates, while representative resistance determinants displayed both broadly distributed and lineage-enriched patterns. Replicon-based plasmid profiling identified 42 plasmid types, including 12 detected in both sources, with IncF-related replicons predominating among these shared profiles. Several food-derived isolates carried multiple plasmid replicon types that were also observed in patient-derived isolates. Overall, food-derived and patient-derived DEC showed partial overlap in genomic backgrounds, resistance determinants, and replicon-defined plasmid profiles within this surveillance setting, while retaining source-associated heterogeneity. These findings should be interpreted as surveillance-based comparative evidence rather than as evidence of direct source attribution or transmission.

Humans↗
PubMed2002

Genomic loss of 18p predicts an adverse clinical outcome in patients with high-risk breast cancer.

The impact of the genomic imbalances on the clinical outcome of 34 patients with lymph-node positive high-risk breast cancer (HRBC) was investigated using comparative genomic hybridization. All of the patients were uniformly treated with high-dose chemotherapy and autologous stem cell transplantation. The average number of chromosomal imbalances per tumor was 11 (range, 2-24), including DNA overrepresentation on chromosomes 1q (59%), 17q (38%), 8q and 16p (35% each), 20q (32%), and 19p (26%), and genomic losses involving 9p and 18q (41%), 8p, 11q, and 18p (38%), 17p (32%), 4p and Xq (29%), and 16q (26%). The most significant association among genomic changes and clinical-pathological features was the correlation of the loss of 8p with progesterone receptor positivity (P < 0.005). With a median follow-up time of 74 months, 15 patients (44%) have relapsed. In the univariate analysis, patients with gain/amplification of 17q including the HER-2/neu gene locus had a longer disease-free survival (P = 0.02), whereas those with genomic loss of 18p had a higher probability of relapse (P = 0.003). In multivariate analysis, the loss of 18p was the only parameter correlated with shorter disease-free survival (relative risk, 4.8; 95% confidence interval, 1.57-14.8; P = 0.006). In summary, our data indicate that the tumoral genomic profile may represent a valuable marker for predicting the clinical outcome in HRBC. Furthermore, the genomic loss of 18p may identify a poor prognostic subgroup of patients with HRBC.

Adult↗