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PubMed2005

From signatures to models: understanding cancer using microarrays.

Genomics has the potential to revolutionize the diagnosis and management of cancer by offering an unprecedented comprehensive view of the molecular underpinnings of pathology. Computational analysis is essential to transform the masses of generated data into a mechanistic understanding of disease. Here we review current research aimed at uncovering the modular organization and function of transcriptional networks and responses in cancer. We first describe how methods that analyze biological processes in terms of higher-level modules can identify robust signatures of disease mechanisms. We then discuss methods that aim to identify the regulatory mechanisms underlying these modules and processes. Finally, we show how comparative analysis, combining human data with model organisms, can lead to more robust findings. We conclude by discussing the challenges of generalizing these methods from cells to tissues and the opportunities they offer to improve cancer diagnosis and management.

Algorithms↗

PubMed2006

Genome-wide analysis of the structural genes regulating defense phenylpropanoid metabolism in Populus.

Salicin-based phenolic glycosides, hydroxycinnamate derivatives and flavonoid-derived condensed tannins comprise up to one-third of Populus leaf dry mass. Genes regulating the abundance and chemical diversity of these substances have not been comprehensively analysed in tree species exhibiting this metabolically demanding level of phenolic metabolism. Here, shikimate-phenylpropanoid pathway genes thought to give rise to these phenolic products were annotated from the Populus genome, their expression assessed by semiquantitative or quantitative reverse transcription polymerase chain reaction (PCR), and metabolic evidence for function presented. Unlike Arabidopsis, Populus leaves accumulate an array of hydroxycinnamoyl-quinate esters, which is consistent with broadened function of the expanded hydroxycinnamoyl-CoA transferase gene family. Greater flavonoid pathway diversity is also represented, and flavonoid gene families are larger. Consistent with expanded pathway function, most of these genes were upregulated during wound-stimulated condensed tannin synthesis in leaves. The suite of Populus genes regulating phenylpropanoid product accumulation should have important application in managing phenolic carbon pools in relation to climate change and global carbon cycling.

Coumaric Acids↗

PubMed2006

Gene Express Inc.

Gene Express, Inc. is a technology-licensing company and provider of Standardized Reverse Transcription Polymerase Chain Reaction (StaRT-PCR) services. Designed by and for clinical researchers involved in pharmaceutical, biomarker and molecular diagnostic product development, StaRT-PCR is a unique quantitative and standardized multigene expression measurement platform. StaRT-PCR meets all of the performance characteristics defined by the US FDA as required to support regulatory submissions [101,102] , and by the Clinical Laboratory Improvement Act of 1988 (CLIA) as necessary to support diagnostic testing [1] . A standardized mixture of internal standards (SMIS), manufactured in bulk, provides integrated quality control wherein each native template target gene is measured relative to a competitive template internal standard. Bulk production enables the compilation of a comprehensive standardized database from across multiple experiments, across collaborating laboratories and across the entire clinical development lifecycle of a given compound or diagnostic product. For the first time, all these data are able to be directly compared. Access to such a database can dramatically shorten the time from investigational new drug (IND) to new drug application (NDA), or save time and money by hastening a substantiated 'no-go' decision. High-throughput StaRT-PCR is conducted at the company's automated Standardized Expression Measurement (SEM) Center. Currently optimized for detection on a microcapillary electrophoretic platform, StaRT-PCR products also may be analyzed on microarray, high-performance liquid chromatography (HPLC), or matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) platforms. SEM Center services deliver standardized genomic data--data that will accelerate the application of pharmacogenomic technology to new drug and diagnostic test development and facilitate personalized medicine.

Gene Expression Profiling↗

PubMed2026

From regionalization to homogenization: Nationwide metagenomic assessment of priority pathogens and the resistome in Polish hospital wastewater.

Hospital wastewater (HWW) is a critical hotspot for the dissemination of antibiotic resistance genes (ARGs) and pathogens. This study provides the first comprehensive metagenomic characterization of HWW across Poland, analyzing 64 medical facilities across two seasons via Nanopore long-read sequencing (total of 128 HWW samples). The HWW microbiome was mostly dominated by Proteobacteria, Bacteroidota, and Firmicutes. Multivariate analysis confirmed a significant seasonal shift in the resistome. Winter samples exhibited geographic regionalization, with localized hotspots of specific ARGs, including vancomycin resistance (operon van) and carbapenemase genes (blaOXA, blaNDM). Conversely, summer samples showed a significant trend toward nationwide homogenization, characterized by a uniform distribution of ESBL genes (blaTEM, blaCTX-M) and multidrug resistance (MDR) determinants, alongside the persistence of localized clinical hotspots. Klebsiella pneumoniae emerged as a central network hub, particularly in summer, showing strong correlations with ESBLs. Quantitative genomic co-occurrence analysis revealed a functional division within dominant taxa: while environmental species like Acinetobacter johnsonii comprised the general background microbiome, clinical pathogens such as Acinetobacter baumannii served as primary vectors, showing frequent associations with high-risk ARGs. Environmental and opportunistic bacteria, such as Aeromonas spp. and Citrobacter spp., were identified as putative 'bridge hosts' associated with mobile resistance determinants and potentially contributing to HGT. The findings indicate that seasonal factors, such as increased temperature and sub-inhibitory antibiotic concentrations, may contribute to the transition from regionalized to homogenized resistance profiles, demonstrating that background resistome convergence can coexist with point-source clinical outbreaks. This seasonal "blurring" of regional boundaries positions HWW as an active vector for large-scale antimicrobial resistance (AMR) dissemination. These results underscore the urgent need for nationwide metagenomic surveillance and advanced wastewater treatment strategies within the "One Health" framework to mitigate the environmental spread of WHO priority pathogens.

Acinetobacter baumannii↗

PubMed2006

Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.

High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration-response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration-response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure-activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>10(5) compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.

Combinatorial Chemistry Techniques↗

PubMed2005

A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses.

Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.

3' Untranslated Regions↗

PubMed2005

In silico chromosomal clustering of genes displaying altered expression patterns in ovarian cancer.

Ovarian cancer, the leading cause of death due to gynecological malignancy, is diagnosed in most cases at an advanced stage. Combined with the paucity of symptoms of early-stage disease, the need to develop novel effective markers for the detection of potentially curable, early-stage disease is self-evident. Comprehensive analyses of somatic gene expression patterns in ovarian cancer were reported previously (n=17) and yielded substantial information on somatically altered genes, information that can potentially be useful in developing early detection markers. To further substantiate the role that these genes play in ovarian cancer tumorogenesis, we surveyed these reports and arranged the significantly altered genes from all reported studies by their chromosomal location (in silico chromosomal clustering). Subsequent comparison of this clustering to known genomic somatic alterations at the DNA level from data obtained using comparative genomic hybridization (CGH) was carried out. The major chromosomal regions that displayed overexpressed genes were correlated with the major CGH-detectable DNA amplification areas at 20q (harboring HE4, SLPI, MYBL2, UBE2C, and SDC4) and 1q (harboring MUC1). These genes may provide insights into ovarian cancer pathogenesis and may also prove to be useful as early detection tools.

Chromosome Mapping↗

PubMed2000

Gene expression profiling in an in vitro model of angiogenesis.

In the present study we have used a novel, comprehensive mRNA profiling technique (GeneCalling) for determining differential gene expression profiles of human endothelial cells undergoing differentiation into tubelike structures. One hundred fifteen cDNA fragments were identified and shown to represent 90 distinct genes. Although some of the genes identified have previously been implicated in angiogenesis, potential roles for many new genes, including OX-40, white protein homolog, KIAA0188, a homolog of angiopoietin-2, ADAMTS-4 (aggrecanase-1), and stanniocalcin were revealed. Support for the biological significance was confirmed by the abrogation of the changes in the expression of angiogenesis inhibitors and in situ hybridization studies. This study has significantly extends the molecular fingerprint of the changes in gene expression that occur during endothelial differentiation and provides new insights into the potential role of a number of new molecules in angiogenesis.

Cells, Cultured↗

PubMed2004

[Transcriptome analysis of virus-infected cells].

Human genome project revealed that human genes are derived from 30,000-40,000 species of genetic loci, which had been estimated as approximately 100,000. The project also promoted devising novel tools that enable us to analyze biological phenomena comprehensively. Microarray technology is a representative of the novel tools in genomics and engages us to explore genome-wide expression levels of genes simultaneously (transcriptome analysis). Here we show transcriptomes obtained from 10 species of cells infected with human cytomegalovirus, as a model virus, by a synthetic DNA microarray system that we have established recently. Our system provides simultaneous and parallel description on alteration of expression of viral and host genes that are represented within a single area on a slide glass. Moreover, we propose a project entitled 'comparative virology on cellular responses of infected hosts' that consists of multiple acquisition and integration of transcriptomes from a combination of several cells and viruses as a panel on the identical platform. The attempt should extract a novel concept in virology from investigation on differences and similarities among influence of a virus on a variety of different cells and conversely among responses of a species of cells against a variety of different viruses.

Cytomegalovirus↗

PubMed2001

A database of protein expression in lung cancer.

We have developed a comprehensive approach to identifying molecular changes in lung cancer that includes both genomic and proteomic analyses. The related effort has produced a large amount of data pertaining to gene expression at the RNA and protein levels. As a result, we have constructed a database that contains protein expression data on lung cancer as well as other relevant data including DNA microarray derived data. A large number of proteins that are expressed in different types of lung cancer have been identified and have been correlated with the expression measures for their corresponding genes at the RNA level. The database is intended to facilitate our effort at developing novel classification schemes for lung cancer and the identification of novel markers for early diagnosis.

Biomarkers, Tumor↗

PubMed2004

HemoPDB: Hematopoiesis Promoter Database, an information resource of transcriptional regulation in blood cell development.

Hematopoiesis describes the process of the normal formation and development of blood cells, involving both proliferation and differentiation from stem cells. Abnormalities in this developmental program yield blood cell diseases, such as leukemia. Although, in recent years, extensive molecular research in normal hematopoietic development has characterized transcription factors and their binding sites in the target gene promoters, the information generated is highly fragmented. In order to integrate this important regulatory information with the corresponding genomic sequences, we have developed a new database called Hematopoiesis Promoter Database (HemoPDB). HemoPDB is a comprehensive resource focused on transcriptional regulation during hematopoietic development and associated aberrances that result in malignancy. HemoPDB (version 1.0) contains 246 promoter sequences and 604 experimentally known cis-regulatory elements of 187 different transcription factors, with links to published references. Orthologous promoters from different species are linked with each other and displayed in the same database record, accompanied by a visual image of the promoters and corresponding annotations of cis-regulatory elements. HemoPDB may be searched for the promoter of a specific gene, transcription factors and target genes, and genes that are expressed in a certain cell type or lineage, through a user-friendly web interface at http://bioinformatics.med.ohio-state.edu/HemoPDB. Links to the documentation and other technical details are provided on this website.

Animals↗

PubMed2002

Subtractive cloning: new genes for studying inflammatory disorders.

Understanding of the biology of interaction between pathogens and host is the central question in studying inflammatory disorders. Subtractive DNA cloning is one of the most efficient and comprehensive methods available for identifying eukaryotic genes regulated under specific physiological conditions, including inflammation and host response. Here we explore the utility of subtractive DNA cloning and describe suppression subtractive hybridization (SSH), a polymerase chain reaction (PCR)-based DNA subtraction method that has been developed and evolved in our labs over several years. The SSH method possesses a number of advantages as compared to other subtractive cloning techniques, making it one of the most adventitious methods for cloning differentially expressed genes. Besides isolation of differentially expressed eukaryotic mRNAs, subtractive DNA cloning can be used to identify genes that are differentially expressed between diverse bacterial species. These genes can be of great interest, as some may encode strain-specific traits such as drug resistance, or bacterial surface proteins involved in determining the virulence of a particular strain. Other genes may be useful as markers for epidemiological or evolutionary studies. To demonstrate the potential of the SSH technique, we describe here the comprehensive characterization of 2 SSH subtracted libraries constructed in our laboratories. One library was created using eukaryotic cDNA subtraction and is specific for mRNAs up-regulated in CD25 positive cells from mouse lymph nodes as compared to CD25 negative cells. The second subtracted library is specific for a methicillin-resistant Staphylococcus aureus bacterial strain, but not in a methicillin-sensitive strain. The bacterial genomes of these 2 strains have been completely sequenced and this second library provides an excellent reference for testing the ability of SSH to recover all strain-specific gene content. The analysis of these 2 subtracted libraries serves as the basis for a discussion of the strength and limitations of the SSH technique. We will also compare and contrast subtractive DNA cloning to other current technologies used to isolate differentially expressed genes.

Animals↗

PubMed2026

Age-related genomic characterization and therapeutic targets in Chinese breast cancer: insights from prospective targeted sequencing and clinical data analysis.

BACKGROUND: In China, breast cancer occurs at a much younger age and has a higher recurrence and mortality rate. However, with changes in lifestyle, there has been a trend towards an older age of breast cancer incidence in Chinese women. There is a paucity of large-scale next-generation sequencing cohorts for the analysis of genomic characterization in these populations and the identification of potential therapeutic targets. METHODS: To address this gap, we performed prospective targeted sequencing of tumor and blood samples from Chinese patients and collected detailed clinical information. We then categorized patients into two groups based on age (< 40 years, n = 637; ≥ 40 years, n = 3442) and proceeded to provide comprehensive descriptions of somatic and germline mutations in both groups. RESULTS: The somatic mutation analysis revealed that PIK3CA, FOXA1, and TBX3 mutations were more prevalent in elderly patients. By leveraging the aforementioned mutational characteristics, we employed our institution's FUTURE-SUPER clinical trial, an umbrella study targeting metastatic breast cancer, to confirm the potential benefits of PI3K-AKT-mTOR pathway inhibitors among elderly patients with breast cancer. Furthermore, TP53 and ERBB2 were more likely to be co-mutated in young women. Patients with TP53 and ERBB2 co-mutation tend to have a poorer prognosis, but through investigation of the SPARK cohort, patients carrying the TP53 and ERBB2 co-mutation are more likely to benefit from immune checkpoint inhibitor combination with tyrosine kinase inhibitor therapy. In our study, we observed a higher frequency of mutations in the DNA homology-dependent recombination pathway in young patients with breast cancer, which was associated with an elevated Ki67 index. Additionally, we confirmed a significant prevalence of germline breast cancer susceptibility gene 1 (gBRCA1) mutations in young patients, whereas germline checkpoint kinase 2 (gCHEK2) mutations are more common in elderly patients. CONCLUSIONS: Our study, which makes use of the largest Chinese breast cancer sequencing cohort, sought to characterize the age-related genomic profile of breast cancer patients and identify novel therapeutic opportunities for individuals with breast cancer.

Adult↗

PubMed2024

Decoding the genetic landscape of allergic rhinitis: a comprehensive network analysis revealing key genes and potential therapeutic targets.

BACKGROUND: Allergic Rhinitis (AR), an inflammatory affliction impacting the upper respiratory tract, has been registering a substantial surge in incidence across the globe. METHODS: We embarked on examination of differentially expressed genes (DEGs) and the Weighted Gene Co-Expression Network Analysis (WGCNA). With this armory of genes identified, we engaged the tools of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Our study continued with the establishment of a protein-protein interaction (PPI) network and the application of LASSO regression. Finally, we leveraged a docking model to elucidate potential drug-gene interactions involving these key genes. RESULTS: Through WGCNA and different express genes screening, PPI network was performed, identifying top 20 key genes, including CD44, CD69, CD274. LASSO regression identified three independent factors, STARD5, CST1, and CHAC1, that were significantly associated with AR. A predictive model was developed with an AUC value over 0.75. Also, 105 potential therapeutic agents were discovered, including Fluorouracil, Cyclophosphamide, Doxorubicin, and Hydrocortisone, offering promising therapeutic strategies for AR. CONCLUSION: By fuzing DEGs with key genes derived from WGCNA, this study has illuminated a comprehensive network of gene interactions involved in the pathogenesis of AR, paving the way for future biomarker and therapeutic target discovery in AR.

Humans↗

PubMed2007

Bacterial DNA microarrays for clinical microbiology: the early logarithmic phase.

In this era of coexistence of high-throughput sequencing technologies and serious difficulties in the management of both common and novel infectious syndromes, new techniques which improve the study of micro-organisms is timely. In bacteriology, the most important subjects are bacterial pathogenicity, discovery of the genomic complexity of bacteria, and the epidemiology of antimicrobial resistance traits. From the clinical point of view, genetic testing is flanking phenotypic testing for the assessment of new, difficult to test antibiotic resistance traits, and for correlations with the microbial behaviour in vivo. The demand for faster, comprehensive and highly parallel microbial diagnostics is also cogent even at the basic laboratory level, where the ultimate objective is saving lives. In this setting, DNA microarrays offer a pivotal contribution by allowing performance of hybridization experiments in highly parallel formats, with an increasing reliability. Not only they are useful in deciphering host and microbial pathophysiology, they can also make the difference in the management of prognostic and therapeutic aspects of many diseases. Here, we provide an overview of the current use and the potential of DNA microarrays in clinical bacteriology, and several applications and technical solutions are discussed.

Bacterial Infections↗

PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗

PubMed2005

arrayCGHbase: an analysis platform for comparative genomic hybridization microarrays.

BACKGROUND: The availability of the human genome sequence as well as the large number of physically accessible oligonucleotides, cDNA, and BAC clones across the entire genome has triggered and accelerated the use of several platforms for analysis of DNA copy number changes, amongst others microarray comparative genomic hybridization (arrayCGH). One of the challenges inherent to this new technology is the management and analysis of large numbers of data points generated in each individual experiment. RESULTS: We have developed arrayCGHbase, a comprehensive analysis platform for arrayCGH experiments consisting of a MIAME (Minimal Information About a Microarray Experiment) supportive database using MySQL underlying a data mining web tool, to store, analyze, interpret, compare, and visualize arrayCGH results in a uniform and user-friendly format. Following its flexible design, arrayCGHbase is compatible with all existing and forthcoming arrayCGH platforms. Data can be exported in a multitude of formats, including BED files to map copy number information on the genome using the Ensembl or UCSC genome browser. CONCLUSION: ArrayCGHbase is a web based and platform independent arrayCGH data analysis tool, that allows users to access the analysis suite through the internet or a local intranet after installation on a private server. ArrayCGHbase is available at http://medgen.ugent.be/arrayCGHbase/.

Base Sequence↗

PubMed2006

Identification of a WRKY protein as a transcriptional regulator of benzylisoquinoline alkaloid biosynthesis in Coptis japonica.

Selected cultured Coptis japonica cells produce a large amount of the benzylisoquinoline alkaloid berberine. Previous studies have suggested that berberine productivity is controlled at the transcript level of biosynthetic genes. We have identified a regulator of transcription in berberine biosynthesis using functional genomics with a transient RNA interference (RNAi) and overexpression of the candidate gene. The 24 primary candidate clones were selected from 1,014 expressed sequence tags (ESTs) that were obtained from a C. japonica cell line producing high levels of berberine. Further characterization of the expression profiles of these ESTs suggested that five ESTs would be good candidates as regulators of berberine production. A newly developed transient RNAi system with C. japonica protoplasts indicated that double-stranded RNA of an EST clone significantly reduced the level of transcripts of 3'-hydroxy N-methylcoclaurine 4'-O-methyltransferase. Sequence analysis showed that this EST encoded a group-II WRKY, and we named it CjWRKY1. When the effects of double-stranded RNA of the CjWRKY1 gene were examined in detail, a marked reduction in the transcripts of all genes involved in berberine biosynthesis was detected, whereas little effect was found in the transcript levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and chorismate mutase (CM) that are associated with primary metabolism. Ectopic expression of CjWRKY1 cDNA in C. japonica protoplasts clearly increased the level of transcripts of all berberine biosynthetic genes examined compared with control treatment, whereas the levels of GAPDH and CM were not affected. The functional role of CjWRKY1 as a specific and comprehensive regulator of berberine biosynthesis is discussed.

Alkaloids↗