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PubMed2002

Dysplastic nodules and hepatocarcinogenesis.

In the last decade, careful examination of explanted cirrhotic livers in liver transplant centers around the world has confirmed the findings of the earlier Japanese investigators: DNs (by this or any other name) represent hepatic, premalignant lesions in chronic liver disease. Careful examination of their gross and microscopic morphologies has led to the hypothesis of precirrhotic, spreading clonal expansions that are resistent to scarring, and that result in neoplastic islands of hepatic parenchyma. The resultant distinctive nodules, often marked by features suggestive of their clonality (such as increased pigment), are at increased risk for subsequent carcinomatous events, thereby giving rise to HCC. Specialized molecular and immunohistochemical studies confirm many aspects of this hypothesis. In suggesting that some aspects of DN pathophysiology are not integral to the carcinogenetic pathway (i.e., inhibition of HSC inactivation), this hypothesis serves a broader purpose, explaining the various settings in which early HCCs are found in cirrhotic explants and in wedge resections of radiographically defined lesions. Discrepancies between Japanese and non-Japanese investigations regarding dysplasia and early HCCs reflect not different biologic pathways but differences in detection, interpretation, and application of nomenclature. These differences may fade away as more international collaborative work brings investigators of diverse nationalities into regular contact, supporting movement toward a commonly acceptable nomenclature and set of diagnostic criteria. Ultimately, an understanding of the pathophysiology of these lesions, through more detailed molecular and physiologic studies, should lead to more efficient and available early detection, and perhaps chemoprevention approaches to hepatic malignancy.

Humans↗
PubMed2026

HeteroGeNETics: Neuroendocrine tumor genetics reflect their heterogeneous complex diversity.

Neuroendocrine neoplasms (NENs) comprise a diverse group of malignancies arising across multiple anatomical sites and displaying remarkable biological and clinical heterogeneity. While advances in sequencing have identified recurrent genetic alterations in several NEN subtypes, these tumors remain largely characterized by a relatively low mutational burden and lack of dominant oncogenic drivers. Consequently, emerging evidence suggests that the molecular basis of neuroendocrine tumorigenesis extends beyond individual mutations and involves broader processes such as chromatin remodeling, telomere maintenance, epigenetic dysregulation and cellular plasticity. This review aims to summarize the current molecular landscape of pulmonary, gastro-enteropancreatic and thymic NENs, focusing on the biological pathways and cellular programs disrupted by recurrent genetic alterations unrelated to syndromes. We discuss how multi-omic studies have refined molecular classification and revealed common principles underlying neuroendocrine tumor development. Collectively, recent literature supports a shift from mutation-centered models toward a more integrated understanding of the complex biology and evolution of NENs.

genomics↗
PubMed2006

A scalable method for integration and functional analysis of multiple microarray datasets.

MOTIVATION: The diverse microarray datasets that have become available over the past several years represent a rich opportunity and challenge for biological data mining. Many supervised and unsupervised methods have been developed for the analysis of individual microarray datasets. However, integrated analysis of multiple datasets can provide a broader insight into genetic regulation of specific biological pathways under a variety of conditions. RESULTS: To aid in the analysis of such large compendia of microarray experiments, we present Microarray Experiment Functional Integration Technology (MEFIT), a scalable Bayesian framework for predicting functional relationships from integrated microarray datasets. Furthermore, MEFIT predicts these functional relationships within the context of specific biological processes. All results are provided in the context of one or more specific biological functions, which can be provided by a biologist or drawn automatically from catalogs such as the Gene Ontology (GO). Using MEFIT, we integrated 40 Saccharomyces cerevisiae microarray datasets spanning 712 unique conditions. In tests based on 110 biological functions drawn from the GO biological process ontology, MEFIT provided a 5% or greater performance increase for 54 functions, with a 5% or more decrease in performance in only two functions.

Algorithms↗
PubMed2006

Identification of interactive gene networks: a novel approach in gene array profiling of myometrial events during guinea pig pregnancy.

OBJECTIVE: The transition from myometrial quiescence to activation is poorly understood, and the analysis of array data is limited by the available data mining tools. We applied functional analysis and logical operations along regulatory gene networks to identify molecular processes and pathways underlying quiescence and activation. STUDY DESIGN: We analyzed some 18,400 transcripts and variants in guinea pig myometrium at stages corresponding to quiescence and activation, and compared them to the nonpregnant (control) counterpart using a functional mapping tool, MetaCore (GeneGo, St Joseph, MI) to identify novel gene networks composed of biological pathways during mid (MP) and late (LP) pregnancy. RESULTS: Genes altered during quiescence and or activation were identified following gene specific comparisons with myometrium from nonpregnant animals, and then linked to curated pathways and formulated networks. The MP and LP networks were subtracted from each other to identify unique genomic events during those periods. For example, changes 2-fold or greater in genes mediating protein biosynthesis, programmed cell death, microtubule polymerization, and microtubule based movement were noted during the transition to LP. CONCLUSION: We describe a novel approach combining microarrays and genetic data to identify networks associated with normal myometrial events. The resulting insights help identify potential biomarkers and permit future targeted investigations of these pathways or networks to confirm or refute their importance.

Animals↗
PubMed2002

Assay and biological relevance of endogenous histamine and its metabolites: application of microseparation techniques.

This review provides an overview of the assay methods used to determine the presence of endogenous histamine (HA) including its metabolites, and also discusses their biological significance. Firstly, this review briefly summarizes the biological significance of HA and its biological pathways. Next, the assay methods with microseparation techniques, such as gas-chromatography (GC), liquid-chromatography (LC), capillary electrophoresis (CE) and capillary electrochromatography (CEC) are looked at from a developmental viewpoint. Finally, the use of these methods, including flow cytometry techniques, for the determination of HA and its metabolites in biological samples, such as blood, urine, brain and cells, is described. The merits and demerits associated with each of these various methods are also discussed, along with their applications.

Animals↗
PubMed2002

Systematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons.

Recent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for ~100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only ~10% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle.

Algorithms↗
PubMed2001

RNA editing by adenosine deaminases that act on RNA.

ADARs are RNA editing enzymes that target double-stranded regions of nuclear-encoded RNA and viral RNA. These enzymes are particularly abundant in the nervous system, where they diversify the information encoded in the genome, for example, by altering codons in mRNAs. The functions of ADARs in known substrates suggest that the enzymes serve to fine-tune and optimize many biological pathways, in ways that we are only starting to imagine. ADARs are also interesting in regard to the remarkable double-stranded structures of their substrates and how enzyme specificity is achieved with little regard to sequence. This review summarizes ongoing investigations of the enzyme family and their substrates, focusing on biological function as well as biochemical mechanism.

3' Untranslated Regions↗
PubMed2000

Nitric oxide reactivity and mechanisms involved in its biological effects.

Nitric oxide (NO) is implicated in many different biological functions. This is due to its widespread distribution in tissue and to its ability to react with a range of molecules in the organism, of which haemoglobin (Hb), soluble guanylyl cyclase (GC), and superoxide anion are of particular note. In this review we describe the biological pathways of NO and their involvement in its physiological effects and toxicity. This endothelial factor rapidly diffuses into the vascular compartment, and the reaction with the Hb haem group is the main metabolic pathway for endogenous NO. Hb is, therefore, a scavenger for this mediator, which prevents it from reaching the tissue components. NO also reacts with the GC haem group, and this combination is fundamental to its acute vasorelaxing effect. Although molecular oxygen plays a very small part in the oxidization process of NO in biological systems, NO reacts with the superoxide anion to generate peroxynitrite at a rate that is limited only by its diffusion coefficient. This reaction is important in pathological conditions because the peroxynitrite thus formed is a selective oxidant and nitrating agent that interacts with numerous biological molecules, thereby damaging them. In addition, of particular note are the interactions of NO with thiol groups, which may mediate several relevant effects in the organism. NO may also activate endogenous ribosyltransferases, which facilitate the transfer of adenosine diphosphate-ribose groups from nicotine adenine dinucleotide to the G protein amino acid residues. These last two processes may also be involved in the control of arterial tone and more precisely so when chronic NO production takes place.

Animals↗
PubMed2004

Match/X, A gene expression pattern recognition algorithm used to identify genes which may be related to CDC2 function and cell cycle regulation.

Large-scale microarray gene expression studies can provide insight into complex genetic networks and biological pathways. A comprehensive gene expression database was constructed using Affymetrix GeneChip microarrays and RNA isolated from more than 6,400 distinct normal and diseased human tissues. These individual patient samples were grouped into over 700 sample sets based on common tissue and disease morphologies, and each set contained averaged expression data for over 45,000 gene probe sets representing more than 33,000 known human genes. Sample sets were compared to each other in more than 750 normal vs. disease pairwise comparisons. Relative up or downregulation patterns of genes across these pairwise comparisons provided unique expression fingerprints that could be compared and matched to a gene of interest using the Match/X trade mark algorithm. This algorithm uses the kappa statistic to compute correlations between genes and calculate a distance score between a gene of interest and all other genes in the database. Using cdc2 as a query gene, we identified several hundred genes that had similar expression patterns and highly correlated distance scores. Most of these genes were known components of the cell cycle involved in G2/M progression, spindle function or chromosome arrangement. Some of the identified genes had unknown biological functions but may be related to cdc2 mediated mechanism based on their closely correlated distance scores. This algorithm may provide novel insights into unknown gene function based on correlation to expression profiles of known genes and can identify elements of cellular pathways and gene interactions in a high throughput fashion.

Algorithms↗
PubMed2006

Diabetic nephropathy is associated with gene expression levels of oxidative phosphorylation and related pathways.

The in vitro behavior of skin fibroblasts from patients with or without diabetic nephropathy is associated with diabetic nephropathy risk. Here we compared skin fibroblast gene expression profiles from two groups of type 1 diabetic patients: 20 with very fast ("fast-track") versus 20 with very slow ("slow-track") rates of development of diabetic nephropathy lesions. Gene expression profiles of skin fibroblasts grown in 25 mmol/l glucose for 36 h were assessed by Affymetrix HG-U133A GeneChips to determine the proportion of genes in a given biological pathway that were directionally consistent in their group differences. Five pathways reached statistical significance. All had significantly greater proportions of genes with higher expression levels in the fast-track group. These pathways, the first four of which are closely related and have overlapping genes, included oxidative phosphorylation (P<0.001), electron transport system complex III (P=0.017), citrate cycle (P=0.037), propanoate metabolism (P=0.044), and transcription factors (P=0.046). These results support the concept that oxidative phosphorylation and related upstream pathways may be important in the pathogenesis of diabetic nephropathy. Whether these findings reflect inherent genetic cellular characteristics, "cell memory," or both requires further study.

Adult↗
PubMed2002

Cancer preventive effects of flavonoids--a review.

A cancer protective effect from plant-derived foods has been found with uncommon consistency in epidemiologic studies. However, it has been difficult to identify specific components responsible for this effect. Many phytochemicals have been shown to be biologically active and they may interact to protect against cancer. In recent years, experimental studies have provided growing evidence for the beneficial action of flavonoids on multiple cancer-related biological pathways (carcinogen bioactivation, cell-signaling, cell cycle regulation, angiogenesis, oxidative stress, inflammation). Although the epidemiologic data on flavonoids and cancer are still limited and conflicting, some protective associations have been suggested for flavonoid-rich foods (soy and premenopausal breast cancer; green tea and stomach cancer; onion and lung cancer). This review focuses on the biological effects of the main flavonoids, as well as the epidemiologic evidence that support their potential cancer protective properties.

Animals↗
PubMed2026

Tumor Loss of the Y Chromosome Defines a Biological Phenotype Associated with Resistance to Radiotherapy Across Cancer Types.

PURPOSE: Sex-linked determinants of radiotherapy response remain poorly understood. We investigated whether tumor loss of the Y chromosome (LOY) is associated with biological and clinical features of radiotherapy resistance across cancer types. MATERIALS AND METHODS: We integrated publicly available cancer cell-line experimental datasets and clinical data to evaluate the impact of LOY on radiotherapy response. The radiosensitivity of 125 cancer cell lines, stratified by Y chromosome status, was analyzed. Gene expression analyses were performed to identify biological pathways associated with LOY. Clinical associations were examined in 537 male patients treated with radiotherapy across multiple tumor types in The Cancer Genome Atlas. RESULTS: LOY was associated with increased post-radiotherapy survival in cancer cell lines (p < 0.001). Transcriptomic analyses demonstrated LOY-associated alterations in DNA damage response, senescence, longevity, and proliferation pathways. In TCGA tumors, LOY was associated with remodeling of the tumor microenvironment, including altered immune and stromal signatures. Clinically, LOY was associated with inferior survival in common-support overlap-weighted analyses adjusted for age, tumor stage, and TCGA-defined tumor type. CONCLUSION: These findings suggest that tumor LOY is associated with a distinct biological profile characterized by features of radioresistance and adverse clinical outcomes following radiotherapy. Further studies are warranted to determine whether LOY represents a clinically relevant sex-linked determinant of radiotherapy response.

loss of Y chromosome↗
PubMed2003

Rad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures.

ATP-binding cassette (ABC)-type ATPases are chemo-mechanical engines for diverse biological pathways. ABC ATPase domains act not only in ABC transporters but also in DNA mismatch, nucleotide excision and double-strand break repair enzymes, as well as in chromosome segregation. Atomic-resolution crystal structures suggest molecular mechanisms for ABC ATPases and reveal surprisingly significant mechanistic and architectural conservation. This emerging unified structural biochemistry provides general medical and biological insights into how ABC proteins function as chemo-mechanical devices. ATP binding by the signature and Q-loop motifs drives the conformations of substrate-specific domains to accomplish diverse functions in transmembrane transport and DNA repair.

ATP-Binding Cassette Transporters↗
PubMed2004

Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression.

DNA microarrays and related tools offer promise for identification of pathways involved in toxic responses to xenobiotics. To be useful for risk assessment, experimental data must be challenged for reliability and interlaboratory reproducibility. Toward this goal, the Hepatotoxicity Working Group of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment evaluated and compared biological and gene expression responses in rats exposed to two model hepatotoxins--clofibrate and methapyrilene. This collaborative effort provided an unprecedented opportunity for the working group to evaluate and compare multiple biological, genomic, and toxicological parameters across different laboratories and microarray platforms. Many of the results from this collaboration are presented in accompanying articles in this mini-monograph, whereas others have been published previously. (Italic)In vivo(/Italic) studies for both compounds were conducted in two laboratories using a standard experimental protocol, and RNA samples were distributed to 16 laboratories for analysis on six microarray platforms. Histopathology, clinical chemistry, and organ weight changes were consistent with reported effects. Gene expression results demonstrated reasonable agreement between laboratories and across platforms. Discrepancies in expression profiles of some individual genes were largely due to platform differences and approaches to data analysis rather than to biological or interlaboratory variability. Despite these discrepancies there was overall agreement in the biological pathways affected by these compounds, demonstrating that transcriptional profiling is reproducible between laboratories and can reliably identify affected pathways necessary to provide mechanistic insight. This effort represents an important first step toward the use of transcriptional profiling in risk assessment.

Animals↗
PubMed2005

Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection.

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.

Animals↗
PubMed2003

Towards understanding the polycystins.

Autosomal dominant polycystic kidney disease (ADPKD) is a very common inherited disease caused by mutations in PKD1 or PKD2 genes characterized by progressive enlargement of fluid-filled cysts and loss of renal function [1]. Previous studies proposed a role for human polycystin-1 in renal morphogenesis acting as a matrix receptor in focal adhesions and for polycystin-2 as a putative calcium channel [2, 3]. The genome of Caenorhabditis elegans contains 2 new members of the polycystin family: lov-1, the homolog for PKD1; and pkd-2, the homolog for PKD2 [4; this paper]. Mutation analysis in C. elegans showed similarly compromised male mating behaviors in all single and double lov-1 and pkd-2 mutants, indicating their participation in a single genetic pathway. Expression analysis localized LOV-1 and PKD-2 to the ends of sensory neurons in male tails and to the tips of CEM neurons in the head, consistent with functions as chemo- or mechanosensors. Human and C. elegans PKD1 and PKD2 homologs, transfected into mammalian renal epithelial cells, co-localized with paxillin in focal adhesions suggesting function in a single biological pathway. Based on the role of polycystins in C. elegans sensory neuron function and the conservation of PKD pathways we suggest that polycystins act as sensors of the extracellular environment, initiating, via focal adhesion assembly, intracellular transduction events in neuronal or morphogenetic processes.

Amino Acid Sequence↗
PubMed2006

Genome-wide differential gene expression in children exposed to air pollution in the Czech Republic.

The Teplice area in the Czech Republic is a mining district where elevated levels of air pollution including airborne carcinogens, have been demonstrated, especially during winter time. This environmental exposure can impact human health; in particular children may be more vulnerable. To study the impact of air pollution in children at the transcriptional level, peripheral blood cells were subjected to whole genome response analysis, in order to identify significantly modulated biological pathways and processes as a result of exposure. Using genome-wide oligonucleotide microarrays, we investigated differential gene expression in children from the Teplice area (n=23) and compared them with children from the rural control area of Prachatice (n=24). In an additional approach, individual gene expressions were correlated with individual peripheral blood lymphocyte micronuclei frequencies, in order to evaluate the linkage of individual gene expressions with an established biomarker of effect that is representative for increased genotoxic risk. Children from the Teplice area showed a significantly higher average micronuclei frequency than Prachatice children (p=0.023). For considerable numbers of genes, the expression differed significantly between the children from the two areas. Amongst these genes, considerable numbers of genes were observed to correlate significantly with the frequencies of micronuclei. The main biological process that appeared significantly affected overall was nucleosome assembly. This suggests an effect of air pollution on the primary structural unit of the condensed DNA. In addition, several other pathways were modulated. Based on the results of this study, we suggest that transcriptomic analysis represents a promising biomarker for environmental carcinogenesis.

Air Pollutants↗
PubMed2001

A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress.

BACKGROUND: Phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] is a key second messenger found ubiquitously in higher eukaryotic cells. The activation of Class I phosphoinositide 3-kinases and the subsequent production of PtdIns(3,4,5)P(3) is an important cell signaling event that has been causally linked to the activation of a variety of downstream cellular processes, such as cell migration and proliferation. Although numerous proteins regulating a variety of biological pathways have been shown to bind PtdIns(3,4,5)P(3), there are no data to demonstrate multiple mechanisms for PtdIns(3,4,5)P(3) synthesis in vivo. RESULTS: In this study, we demonstrate an alternative pathway for the in vivo production of PtdIns(3,4,5)P(3) mediated by the action of murine Type Ialpha phosphatidylinositol 4-phosphate 5-kinase (Type Ialpha PIPkinase), an enzyme best characterized as regulating cellular PtdIns(4,5)P(2) levels. Analysis of this novel pathway of PtdIns(3,4,5)P(3) synthesis in cellular membranes leads us to conclude that in vivo, Type Ialpha PIPkinase also acts as a PtdIns(3,4)P(2) 5-kinase. We demonstrate for the first time that cells actually contain an endogenous PtdIns(3,4)P(2) 5-kinase, and that during oxidative stress, this enzyme is responsible for PtdIns(3,4,5)P(3) synthesis. Furthermore, we demonstrate that by upregulating the H(2)O(2)-induced PtdIns(3,4,5)P(3) levels using overexpression studies, the endogenous PtdIns(3,4)P(2) 5-kinase is likely to be Type Ialpha PIPkinase. CONCLUSIONS: We describe for the first time a novel in vivo activity for Type Ialpha PIPkinase, and a novel pathway for the in vivo synthesis of functional PtdIns(3,4,5)P(3), a key lipid second messenger regulating a number of diverse cellular processes.

Animals↗