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PubMed2004

Gene expression profiles of transcription factors and signaling molecules in the ascidian embryo: towards a comprehensive understanding of gene networks.

Achieving a real understanding of animal development obviously requires a comprehensive rather than partial identification of the genes working in each developmental process. Recent decoding of genome sequences will enable us to perform such studies. An ascidian, Ciona intestinalis, one of the animals whose genome has been sequenced, is a chordate sharing a basic body plan with vertebrates, although its genome contains less paralogs than are usually seen in vertebrates. In the present study, we discuss the genomewide approach to networks of developmental genes in Ciona embryos. We focus on transcription factor genes and some major groups of signal transduction genes. These genes are comprehensively listed and examined with regard to their embryonic expression by in situ hybridization (http://ghost.zool.kyoto-u.ac.jp/tfst.html). The results revealed that 74% of the transcription factor genes are expressed maternally and that 56% of the genes are zygotically expressed during embryogenesis. Of these, 34% of the transcription factor genes are expressed both maternally and zygotically. The number of zygotically expressed transcription factor genes increases gradually during embryogenesis. As an example, and taking advantage of this comprehensive description of gene expression profiles, we identified transcription factor genes and signal transduction genes that are expressed at the early gastrula stage and that work downstream of beta-catenin, FoxD and/or Fgf9/16/20. Because these three genes are essential for ascidian endomesoderm specification, transcription factor genes and signal transduction genes involved in each of the downstream processes can be deduced comprehensively using the present approach.

Animals↗
PubMed2001

Individual metabolism should guide agriculture toward foods for improved health and nutrition.

Genomics and bioinformatics have the vast potential to identify genes that cause disease by investigating whole-genome databases. Comparison of an individual's geno-type with a genomic database will allow the prescription of drugs to be tailored to an individual's genotype. This same bioinformatic approach, applied to the study of human metabolites, has the potential to identify and validate targets to improve personalized nutritional health and thus serve to define the added value for the next generation of foods and crops. Advances in high-throughput analytic chemistry and computing technologies make the creation of a vast database of metabolites possible for several subsets of metabolites, including lipids and organic acids. In creating integrative databases of metabolites for bioinformatic investigation, the current concept of measuring single biomarkers must be expanded to 3 dimensions to 1) include a highly comprehensive set of metabolite measurements (a profile) by multiparallel analyses, 2) measure the metabolic profile of individuals over time rather than simply in the fasted state, and 3) integrate these metabolic profiles with genomic, expression, and proteomic databases. Application of the knowledge of individual metabolism will revolutionize the ability of nutrition to deliver health benefits through food in the same way that knowledge of genomics will revolutionize individual treatment of dis-ease with pharmaceuticals.

Biomarkers↗
PubMed2026

Agricultural sprinkler irrigation systems as environmental reservoirs and airborne dissemination sources of Legionella pneumophila.

Sprinkler irrigation systems are critical for modern agriculture but represent largely unrecognized aquatic environments capable of sustaining opportunistic human pathogens. Among them, Legionella pneumophila is of particular concern due to its ability to colonize engineered water systems, persist under fluctuating environmental conditions, and be transmitted through aerosols. In this study, we conducted a comprehensive microbiological and genomic investigation of irrigation ponds and ditches in a rural area of north-east Spain where two zones were sampled. Metagenomic profiling revealed highly diverse microbial communities encompassing more than 20,000 species, including 21 airborne-transmissible bacterial pathogens of clinical relevance. Notably, L. pneumophila was detected in both zones, with a relative abundance of up to 4.6 %. Culture-based isolation confirmed the presence of L. pneumophila serogroup 1, Pontiac group, Benidorm subgroup, sequence type 15. Phylogenetic analysis demonstrated a close relationship between this environmental strain and clinical isolates obtained during a Legionnaires' disease outbreak occurred in 2015, which had remained without a confirmed environmental source. Meteorological data from the exposure period revealed wind conditions favouring long-distance aerosol dispersion from irrigated fields toward residential areas. Our findings provide evidence that irrigation infrastructures can act as environmental reservoirs and dissemination routes of L. pneumophila among other airborne pathogens. These results underscore the need to incorporate agricultural irrigation systems into routine environmental surveillance, outbreak investigations, and public health risk assessments.

Legionella pneumophila↗
PubMed2005

Regio- and stereospecific analysis of glycerolipids.

In recent years researchers have recognized the potential value of comprehensive lipid profiling (lipidomics), which was invented and promoted by lipidologists who recognized the many valuable applications that grew out of the fields of DNA profiling (genomics) and protein profiling (proteonomics). Through lipid class-selective intrasource ionization and subsequent analysis of two-dimensional cross-peak intensities, the chemical identity and mass composition of individual molecular species of most lipid classes can now be determined in a chloroform extract. There remains, however, the necessity to distinguish the enantiomers and isobaric regioisomers resulting from enzymatic and chemical reactions, which conventional high performance liquid chromatography/mass spectrometry (HPLC/MS) has been slow to accommodate, and tandem MS unable to provide. While reversed-phase HPLC can separate regioisomers, normal-phase HPLC can resolve diastereomers, and chiral-phase HPLC can effect dramatic resolution of enantiomers, the full potential of the combined systems has seldom been exploited. The present chapter calls attention to both recent and earlier combinations of these methodologies with mass spectrometry, which allows the HPLC/ESI (electrospray ionization)-MS/MS separation and identification of enantiomeric diacylglycerols, triacylglycerols, and glycerophospholipids as well as their isobaric regioisomers. These developments permit further expansion of lipid profiling (lipidomics) and better understanding of lipid metabolism.

Biochemistry↗
PubMed2025

Pharmacogenomic insights into angiotensin converting enzyme inhibitors and calcium channel blockers for personalized hypertension treatment.

Arterial hypertension is a complex disorder influenced by extensive genetic variability, which contributes to interindividual differences in drug response by altering metabolism, transport, and receptor interaction. Current antihypertensive therapies effectively control arterial hypertension in only about half of patients, emphasizing the need for precise strategies. Genetic variation plays a crucial role in modulating drug response, and integrating this knowledge into clinical practice could significantly transform the management of hypertension through personalized medicine. This review examines the impact of genetic factors on the efficacy of antihypertensive drug classes, including angiotensin converting enzyme inhibitors and calcium channel blockers. It also examines advances in pharmacogenomic research that can aid in tailoring drug selection and dose adjustment based on genetic profiles. Beyond genomics, this review also highlights the impact of multiomics approaches, such as proteomics, metabolomics, and microbiomics, in advancing precision medicine and enabling a comprehensive, personalized approach to hypertension management. Pharmacogenomics can help refine hypertension care, improve patient outcomes, and reduce the burden of the disease. The future of hypertension treatment lies in precision medicine, where therapy is tailored to individual needs for effective and personalized management.

Humans↗
PubMed2026

Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer.

PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer; however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. EXPERIMENTAL DESIGN: We analyzed a prospectively maintained cohort of 1,254 patients with histologically confirmed biliary tract cancer who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing (NGS) assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. RESULTS: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, and gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2-and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. CONCLUSIONS: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted NGS of biliary tract cancer and affirms the use of precision medicine in patients with these diseases. Genomic heterogeneity and therapeutic resistance observed in this study has the potential to inform ongoing drug development efforts for biliary tract cancer.

Humans↗
PubMed2006

SAGE analysis to identify embryonic stem cell-predominant transcripts.

The Human Genome Consortium has successfully sequenced the entire human genome (http://www.genome.gov/11006945), but an unfinished goal remains the identification of specific genes responsible for unique cellular processes. With respect to embryonic stem (ES) cells, this includes the identification of factors that govern self-renewal and pluripotentiality. One technique that facilitates this last goal is serial analysis of gene expression (SAGE), a functional genomics technique that identifies and quantifies mRNA transcripts. This technique relies on the preparation and sequencing of complementary DNA concatemers to rapidly generate a comprehensive profile of gene expression within a cell, and unlike microarrays, it does not require prior knowledge of the genes to be assayed. Because SAGE is a sequence-based technique, it can be used to search for ES-restricted genes (i.e., markers) by sequence comparisons among stem cells, differentiated cells, and tissues. These markers can then be genetically manipulated to understand the molecular basis for stem cell biology to help define how transcriptional mechanisms distinguish ES cells from other, less-pluripotent cell types. SAGE is, thus, a powerful technique that permits a comprehensive analysis of mRNA abundance that can define, at a molecular level, fundamental characteristics of ES cells. In this chapter, we illustrate the basic principles of SAGE, describe a complete protocol for the generation of SAGE libraries, and show how this technique can be employed to analyze embryonic stem cells.

Animals↗
PubMed2003

What can digital transcript profiling reveal about human cancers?

Important biological and clinical features of malignancy are reflected in its transcript pattern. Recent advances in gene expression technology and informatics have provided a powerful new means to obtain and interpret these expression patterns. A comprehensive approach to expression profiling is serial analysis of gene expression (SAGE), which provides digital information on transcript levels. SAGE works by counting transcripts and storing these digital values electronically, providing absolute gene expression levels that make historical comparisons possible. SAGE produces a comprehensive profile of gene expression and can be used to search for candidate tumor markers or antigens in a limited number of samples. The Cancer Genome Anatomy Project has created a SAGE database of human gene expression levels for many different tumors and normal reference tissues and provides online tools for viewing, comparing, and downloading expression profiles. Digital expression profiling using SAGE and informatics have been useful for identifying genes that have a role in tumor invasion and other aspects of tumor progression.

Antigens, Neoplasm↗
PubMed2001

Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer.

The biological significance of DNA amplification in cancer is thought to be due to the selection of increased expression of a single or few important genes. However, systematic surveys of the copy number and expression of all genes within an amplified region of the genome have not been performed. Here we have used a combination of molecular, genomic, and microarray technologies to identify target genes for 17q23, a common region of amplification in breast cancers with poor prognosis. Construction of a 4-Mb genomic contig made it possible to define two common regions of amplification in breast cancer cell lines. Analysis of 184 primary breast tumors by fluorescence in situ hybridization on tissue microarrays validated these results with the highest amplification frequency (12.5%) observed for the distal region. Based on GeneMap'99 information, 17 known genes and 26 expressed sequence tags were localized to the contig. Analysis of genomic sequence identified 77 additional transcripts. A comprehensive analysis of expression levels of these transcripts in six breast cancer cell lines was carried out by using complementary DNA microarrays. The expression patterns varied from one cell line to another, and several overexpressed genes were identified. Of these, RPS6KB1, MUL, APPBP2, and TRAP240 as well as one uncharacterized expressed sequence tag were located in the two common amplified regions. In summary, comprehensive analysis of the 17q23 amplicon revealed a limited number of highly expressed genes that may contribute to the more aggressive clinical course observed in breast cancer patients with 17q23-amplified tumors.

Breast Neoplasms↗
PubMed2005

Alteration in gene expression profile by full-length hepatitis B virus genome.

Persistent expression of hepatitis B virus (HBV) proteins is thought to be involved in virus-related hepatocarcinogenesis. Here, we compared the gene expression profile of cells persistently expressing the full-length HBV with that of negative control cells to comprehensively investigate virus-mediated changes in the gene expression of the host cells. RNA samples from both virus-expressing and negative control cells were used for the DNA array assay. DNA array assay and subsequent corroboration assays revealed that expression of 14 of 1,176 genes (1.2%) was altered in response to virus expression. The upregulated genes included CD44, high mobility group protein-I, thymosin beta-10 and 27-kD heat shock protein, while the downregulated genes included NM23-H1, all of which are thought to be associated with the development or progression of carcinoma in the liver or other organs. Furthermore, virus expression resulted in the decrease of two apoptosis-inducing molecules, caspase-3 and BAX, which may also contribute to carcinogenesis through prolonged survival of the host cell. Thus, expression of the virus genome caused carcinogenesis-related changes in host cell gene expression. HBV expression may change the host cell to a malignant phenotype through alterations in the expression levels of a set of genes.

Blotting, Western↗
PubMedDate not supplied

The potentials of MS-based subproteomic approaches in medical science: the case of lysosomes and breast cancer.

Because of the great number of women who are diagnosed with breast cancer each year, and though this disease presents the lowest mortality rate among cancers, breast cancer remains a major public health problem. As for any cancer, the tumorigenic and metastatic processes are still hardly understood, and the biochemical markers that allow either a precise monitoring of the disease or the classification of the numerous forms of breast cancer remain too scarce. Therefore, great hopes are put on the development of high-throughput genomic and proteomic technologies. Such comprehensive techniques should help in understanding the processes and in defining steps of the disease by depicting specific genes or protein profiles. Because techniques dedicated to the current proteomic challenges are continuously improving, the probability of the discovery of new potential protein biomarkers is rapidly increasing. In addition, the identification of such markers should be eased by lowering the sample complexity; e.g., by sample fractionation, either according to specific physico-chemical properties of the proteins, or by focusing on definite subcellular compartments. In particular, proteins of the lysosomal compartment have been shown to be prone to alterations in their localization, expression, or post-translational modifications (PTMs) during the cancer process. Some of them, such as the aspartic protease cathepsin D (CatD), have even been proven as participating actively in the disease progression. The present review aims at giving an overview of the implication of the lysosome in breast cancer, and at showing how subproteomics and the constantly refining MS-based proteomic techniques may help in making breast cancer research progress, and thus, hopefully, in improving disease treatment.

Biomarkers, Tumor↗
PubMed2025

Mutational scanning of TnpB reveals latent activity for genome editing.

TnpB is a diverse family of RNA-guided endonucleases associated with prokaryotic transposons. Due to their small size and putative evolutionary relationship to CRISPR-Cas12, TnpB enzymes hold significant potential for genome editing. However, most TnpBs lack robust gene editing activity, and unbiased profiling of mutational effects on editing activity has not been explored. Here, we mapped comprehensive sequence-function landscapes of a TnpB ribonucleoprotein and discovered many activating mutations in both the protein and RNA. One- and two-position RNA mutants outperform existing variants, highlighting the utility of systematic RNA scaffold mutagenesis. Leveraging the protein's mutational landscape, we identified enhanced TnpB variants from a combinatorial library of activating mutations. These variants enhanced editing in human cells, N. benthamiana, pepper, and rice, with up to a fifty-fold increase compared to wild-type TnpB. These findings highlight previously unknown elements critical for regulating TnpB endonuclease activity and reveal surprising latent activity accessible through mutation.

Journal Article↗
PubMed2003

Comprehensive proteomic profiling of the membrane constituents of a Mycobacterium tuberculosis strain.

Mycobacterium tuberculosis is an infectious microorganism that causes human tuberculosis. The cell membranes of pathogens are known to be rich in possible diagnostic and therapeutic protein targets. To compliment the M. tuberculosis genome, we have profiled the membrane protein fraction of the M. tuberculosis H37Rv strain using an analytical platform that couples one-dimensional SDS gels to a microcapillary liquid chromatography-nanospray-tandem mass spectrometer. As a result, 739 proteins have been identified by two or more distinct peptide sequences and have been characterized. Interestingly, approximately 450 proteins represent novel identifications, 79 of which are membrane proteins and more than 100 of which are membrane-associated proteins. The physicochemical properties of the identified proteins were studied in detail, and then biological functions were obtained by sorting them according to Sanger Institute gene function category. Many membrane proteins were found to be involved in the cell envelope, and those proteins with energy metabolic functions were also identified in this study.

Amino Acid Sequence↗
PubMed2004

Deciphering gene expression profiles generated from DNA microarrays and their applications in oral medicine.

Genome-wide monitoring of gene expression profiles using DNA microarrays provides a unique approach to exploring the biological processes underlying oral diseases and disorders by providing a comprehensive survey of a cell's or tissue's transcriptional mapping. This revolutionary technology allows for the simultaneous assessment of the transcription levels of tens of thousands of genes, and of their relative expression between normal and diseased cells. As microarray data analysis evolves, there is a widespread hope that microarrays will significantly impact our ability to explore the genetic changes associated with disease etiology and development, ultimately leading to the discovery of new biomarkers for disease diagnosis and prognosis prediction as well as new therapeutic tools. The goal of this manuscript is to review 2 of the most commonly used microarray technologies, provide an overview of data analyses involved in a typical microarray experiment, and comment upon the application of microarrays to oral medicine.

Biomarkers↗
PubMed2025

APAV: An advanced pangenome analysis and visualization toolkit.

Traditional pangenome analysis focuses on gene presence/absence variations (gene PAVs). However, the current methods for gene PAV analysis are insensitive to detect small but valuable mutations within gene regions, and they overlook variations in intergenic regions. Additionally, the visual inspection of PAVs is an important but time-consuming step for pangenome analysis and result interpretation. To address these issues, we present APAV, an advanced toolkit designed for comprehensive PAV analysis and visualization. It integrates gene element-level PAV analysis and provides PAV analysis for arbitrary given regions in a genome. The resulted PAV profile can be visualized and investigated interactively with reports in HTML format, enabling researchers to conveniently verify sequencing read depth, target region coverage, and intervals of absence for each PAV. Furthermore, APAV offers various subsequent analysis and visualization functions based on the PAV profile table, including basic statistics, sample clustering, genome size estimation, and phenotype association analysis. We demonstrated the capability of APAV with pangenome analysis of tumor genomes and rice genomes. Performing PAV analysis at the element level not only provides more accurate information about the variations but also uncovers a larger number of variations for the phenotype-genotype association studies. In the rice genome analysis, we identified over twenty thousand distributed genes and more than fifty thousand distributed genetic elements. In the tumor genome analysis, element-level analysis revealed approximately three times as many phenotype-related genes as gene-level analysis. This indicates that altering the PAV unit from genes to smaller segments or elements can lead to more biological insights.

Software↗
PubMed2026

Molecular subtyping of adrenocortical carcinoma reveals distinct subtypes with prognostic and therapeutic implications.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with poor survival and limited treatment options. To comprehensively characterize its molecular landscape and identify clinically relevant subtypes, we performed an integrated genomic analysis - including whole-exome sequencing, RNA sequencing, and copy number variation profiling - on 61 Chinese patients with ACC. We identified recurrent mutations in TP53 (25%), CTNNB1 (15%), ZNRF3 (10%), and MEN1 (8%). Unsupervised clustering of transcriptomic data revealed four distinct molecular subtypes: cortisol-driven (CD, 14%), immune-suppressed (IS, 40%), cell cycle-altered (CCA, 22%), and immunomodulatory (IM, 24%). The CD subtype exhibited steroidogenic pathway activation; the IS subtype showed T cell receptor downregulation and the worst disease-free survival; the CCA subtype was marked by chromosomal instability and cell cycle gene overexpression; and the IM subtype displayed enriched immune signaling and favorable outcomes. Copy number analysis further uncovered focal amplifications (e.g. TERT, CDK4) and HLA-II deletions. This study establishes a novel molecular classification of ACC, providing a framework for subtype-specific therapeutic strategies, such as CDK4/6 inhibition for CCA and immunotherapy for IM tumors, while highlighting the clinical challenges of immune-cold IS tumors.

Humans↗
PubMed2003

Comparative microarray analysis of gene expression during activation of human peripheral blood T cells and leukemic Jurkat T cells.

Activation of T cells involves a complex cascade of signal transduction pathways linking T-cell receptor engagement at the cell membrane to the transcription of multiple genes within the nucleus. The T-cell leukemia-derived cell line Jurkat has generally been used as a model system for the activation of T cells. However, genome-wide comprehensive studies investigating the activation status, and thus the appropriateness, of this cell line for this purpose have not been performed. We sought to compare the transcriptional profiles of phenotypically purified human CD2(+) T cells with those of Jurkat T cells during T-cell activation, using cDNA microarrays containing 6912 genes. About 300 genes were up-regulated by more than 2-fold during activation of both peripheral blood (PB) T cells and Jurkat T cells. The number of down-regulated genes was significantly lower than that of up-regulated genes. Only 79 genes in PB T cells and 37 genes in Jurkat T cells were down-regulated by more than 2-fold during activation. Comparison of gene expression during activation of Jurkat and PB T cells revealed a common set of genes that were up-regulated, such as Rho GTPase-activating protein 1, SKP2, CDC25A, T-cell specific transcription factor 7, cytoskeletal proteins, and signaling molecules. Genes that were commonly down-regulated in both PB T cells and Jurkat T cells included CDK inhibitors (p16, p19, p27), proapoptotic caspases, and the transcription factors c-fos and jun-B. After activation, 71 genes in PB T cells and only 3 genes in Jurkat T cells were up-regulated 4-fold or more. Of these up-regulated genes and expressed sequence tags, 44 were constitutively expressed at high levels in nonactivated Jurkat cells. Quantitative real-time RT-PCR analysis confirmed our microarray data. Our findings indicate that although there is significant overlap in the activation-associated transcriptional profiles in PB T cells compared with Jurkat T cells, there is a subset of genes showing differential expression patterns during the activation of the two cell types.

Antigens, CD↗
PubMed2006

Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer.

BACKGROUND: Thymidylate synthase (TS) is a critical target for cancer chemotherapy and is one of the most extensively studied biomarkers for fluoropyrimidine-based chemotherapy. In addition to its critical role in enzyme catalysis, TS functions as an RNA binding protein to regulate the expression of its own mRNA translation and other cellular mRNAs, such as p53, at the translational level. In this study, a comprehensive gene expression analysis at the levels of both transcriptional and post-transcriptional regulation was conducted to identify response markers using human genome array with TS-depleted human colon cancer HCT-C18 (TS-) cells and HCT-C18 (TS+) cells stably transfected with the human TS cDNA expression plasmid. RESULTS: A total of 38 genes were found to be significantly affected by TS based on the expression profiles of steady state mRNA transcripts. However, based on the expression profiles of polysome associated mRNA transcripts, over 149 genes were affected by TS overexpression. This indicates that additional post-transcriptionally controlled genes can be captured with profiling polysome associated mRNA population. This unique approach provides a comprehensive overview of genes affected by TS. Additional novel post-transcriptionally regulated genes affected by 5-fluorouracil (5-FU) treatment were also discovered via similar approach. CONCLUSION: To our knowledge, this is the first time that a comprehensive gene expression profile regulated by TS and 5-FU was analyzed at the multiple steps of gene regulation. This study will provide candidate markers that can be potentially used for predicting therapeutic outcomes for fluoropyrimidine-based cancer chemotherapy.

Antimetabolites, Antineoplastic↗