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PubMed2006

Integrated molecular signature of disease: analysis of influenza virus-infected macaques through functional genomics and proteomics.

Recent outbreaks of avian influenza in humans have stressed the need for an improved nonhuman primate model of influenza pathogenesis. In order to further develop a macaque model, we expanded our previous in vivo genomics experiments with influenza virus-infected macaques by focusing on the innate immune response at day 2 postinoculation and on gene expression in affected lung tissue with viral genetic material present. Finally, we sought to identify signature genes for early infection in whole blood. For these purposes, we infected six pigtailed macaques (Macaca nemestrina) with reconstructed influenza A/Texas/36/91 virus and three control animals with a sham inoculate. We sacrificed one control and two experimental animals at days 2, 4, and 7 postinfection. Lung tissue was harvested for pathology, gene expression profiling, and proteomics. Blood was collected for genomics every other day from each animal until the experimental endpoint. Gross and microscopic pathology, immunohistochemistry, viral gene expression by arrays, and/or quantitative real-time reverse transcription-PCR confirmed successful yet mild infections in all experimental animals. Genomic experiments were performed using macaque-specific oligonucleotide arrays, and high-throughput proteomics revealed the host response to infection at the mRNA and protein levels. Our data showed dramatic differences in gene expression within regions in influenza virus-induced lesions based on the presence or absence of viral mRNA. We also identified genes tightly coregulated in peripheral white blood cells and in lung tissue at day 2 postinoculation. This latter finding opens the possibility of using gene expression arrays on whole blood to detect infection after exposure but prior to onset of symptoms or shedding.

Animals↗

PubMed2005

Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity.

OBJECTIVE: To examine the potential usefulness of a novel thermal imaging technique to evaluate and monitor inflammatory arthritis activity in small joints using rat models, and to determine whether thermal changes can be used to detect preclinical stages of synovitis. METHODS: Three different rat strains were studied in a model of inflammatory arthritis of the ankle induced by an intra-articular (IA) injection of complete Freund's adjuvant (CFA), compared with the contralateral ankle injected with normal saline. Arthritis activity and severity scores, ankle diameters, pain related posture scores, and thermal images were obtained at 10 different times between 0 h (before induction) and day 7. The pristane induced arthritis (PIA) model was used to study preclinical synovitis. Thermal images were obtained at each time point using the TSA ImagIR system and were digitally analysed. RESULTS: Rats developed similar ankle arthritis detected six hours after the IA injection of CFA, which persisted for seven days. All ankle clinical indices, including arthritis activity and severity scores, correlated significantly with ankle thermal imaging changes in the monoarthritis model (p<0.003). No thermal imaging changes were detected in preclinical stages of PIA. However, PIA onset coincided with increased ankle thermal signature. CONCLUSIONS: Thermal measurements correlated significantly with arthritis activity and severity indices. The technique was highly sensitive and could measure directly two cardinal signs of inflammation (warmth and oedema, based on ankle diameter) in an area (ankle) that is less than half the size of a human interphalangeal joint, suggesting a potential use in drug trials or clinical practice.

Animals↗

PubMed2007

Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause. AIM: To identify peripheral blood (PB) gene expression profiles that may distinguish RA subtypes. METHODS: Large-scale expression profiling by cDNA microarrays was performed on PB from 35 patients and 15 healthy individuals. Differential gene expression was analysed by significance analysis of microarrays (SAM), followed by gene ontology analysis of the significant genes. Gene set enrichment analysis was applied to identify pathways relevant to disease. RESULTS: A substantially raised expression of a spectrum of genes involved in immune defence was found in the PB of patients with RA compared with healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in patients with RA compared with healthy individuals, which was confirmed by gene ontology and pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFN(high) patients). Application of pathway analysis revealed that the IFN(high) group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFN(low) group was similar to the controls. CONCLUSION: The IFN type I signature defines a subgroup of patients with RA, with a distinct biomolecular phenotype, characterised by increased activity of the innate defence system, coagulation and complement cascades, and fatty acid metabolism.

Adult↗

PubMed1996

Fractal signature analysis measures cancellous bone organisation in macroradiographs of patients with knee osteoarthritis.

OBJECTIVE: To determine whether fractal signature analysis (FSA) of digitised macroradiographs of knees quantifies alterations in trabecular structure in the tibial cancellous bone of osteoarthritic patients with either early or definite joint space narrowing compared with non-arthritic subjects. METHODS: 90 osteoarthritic knees had macroradiographs at x5 magnification. Joint space width and FSA of horizontal and vertical trabecular organisation in the tibial subarticular cancellous bone were measured in the medial and lateral tibio-femoral compartments and compared to reference values obtained from the knees of 14 healthy non-arthritic volunteers, and to the subject's age and weight. RESULTS: Compared to the non-arthritic joints, FSA of the trabecular structure of the medial diseased compartment of the tibia was significantly different and correlated with the degree of joint space narrowing (P < 0.003); FSA of horizontal trabecular structures decreased (P < 0.001) in knees with early osteoarthritis (joint space > 3 mm) and vertical trabecular FSA increased in knees with marked joint space narrowing (joint space < 3 mm). In the lateral compartment of the tibia, FSA did not show a difference between any of the categories. With increasing age of all subjects, the changes in FSA indicated a significant increase in the number of fine horizontal and vertical trabeculae. No correlation was found between the subjects' body weight and changes in the subarticular cancellous bone organisation. CONCLUSIONS: FSA quantifies changes in cancellous bone organisation in knee osteoarthritis. In the diseased compartment, increased horizontal trabecular thickness occurred early and preceded the later changes in the vertical structures.

Age Factors↗

PubMed2026

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

COLONIC POLYPS↗

PubMed1979

Tissue signatures with dual-energy computed tomography.

By providing information on two parameters, dual-energy computed tomography can offer clinically useful tissue signatures for metallic deposits (Ca) or injected iodine, as well as for different normal and abnormal types of brain parenchymal tissues and CSF. Cerebral CT was performed on 36 patients and tissue differences analyzed using Hounsfield notation.

Brain↗

PubMed2004

Neural signature of taste familiarity in the gustatory cortex of the freely behaving rat.

Ample data indicate that the gustatory cortex (GC) subserves the processing, encoding, and storage of taste information. To further elucidate the neural processes involved, we recorded multi-unit activity in the GC of the freely behaving rat as it became familiar with a novel tastant. Exposure to the tastant was performed over three 40- to 50-min sessions, 24 h apart. In each session, the tastant was presented repeatedly, 1 s at a time, with 10- to 12-s inter-trial intervals. The neural response to the tastant typically lasted 7 s. Our results show that the average neuronal response to the tastant increased as this tastant became familiar, but this increase was detected only during the last 5 s of the response. The increased response was not generalized to another tastant. Furthermore, our analysis suggests that specific neuronal populations subserve the processing of familiarity of specific tastants. The signature of familiarity was not detected in the course of the familiarization session, but only on the subsequent day, suggesting that its development involves slow post-acquisition processes. Our data are in line with the notion that GC neurons process multiple taste attributes, familiarity included, during different temporal phases of their response. The data also suggest that by default the brain considers a taste stimulus as novel, unless proven otherwise.

Animals↗

PubMed2003

Biophysical properties and ionic signature of neuronal progenitors of the postnatal subventricular zone in situ.

Previous studies have reported the presence of neuronal progenitors in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the postnatal mammalian brain. Although many studies have examined the survival and migration of progenitors after transplantation and the factors influencing their proliferation or differentiation, no information is available on the electrophysiological properties of these progenitors in a near-intact environment. Thus we performed whole cell and cell-attached patch-clamp recordings of progenitors in brain slices containing either the SVZ or the RMS from postnatal day 15 to day 25 mice. Both regions displayed strong immunoreactivity for nestin and neuron-specific class III beta-tubulin, and recorded cells displayed a morphology typical of the neuronal progenitors known to migrate throughout the SVZ and RMS to the olfactory bulb. Recorded progenitors had depolarized zero-current resting potentials (mean more depolarized than -28 mV), very high input resistances (about 4 GOmega), and lacked action potentials. Using the reversal potential of K+ currents through a cell-attached patch a mean resting potential of -59 mV was estimated. Recorded progenitors displayed Ca2+-dependent K+ currents and TEA-sensitive-delayed rectifying K+ (KDR) currents, but lacked inward K+ currents and transient outward K+ currents. KDR currents displayed classical kinetics and were also sensitive to 4-aminopyridine and alpha-dendrotoxin, a blocker of Kv1 channels. Na+ currents were found in about 60% of the SVZ neuronal progenitors. No developmental changes were observed in the passive membrane properties and current profile of neuronal progenitors. Together these data suggest that SVZ neuronal progenitors display passive membrane properties and an ionic signature distinct from that of cultured SVZ neuronal progenitors and mature neurons.

Animals↗

PubMed2004

Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter.

Little is known about global gene expression patterns in the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). To address this, we used high-density oligonucleotide microarray technology to compare expression levels of approximately 6,800 genes in postmortem spinal cord gray matter obtained from individuals with ALS as well as normal individuals. Using Fisher discriminant analysis (FDA) and leave-one-out cross-validation (LOOCV), we discerned an ALS-specific signature. Moreover, it was possible to distinguish familial ALS (FALS) from sporadic ALS (SALS) gene expression profiles. Characterization of the specific genes significantly altered in ALS uncovered a pro-inflammatory terminal state. Moreover, we found alterations in genes involved in mitochondrial function, oxidative stress, excitotoxicity, apoptosis, cytoskeletal architecture, RNA transcription and translation, proteasomal function, and growth and signaling. It is apparent from this study that DNA microarray analysis and appropriate bioinformatics can reveal distinct phenotypic changes that underlie the terminal stages of neurodegeneration in ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Potential cellular signatures of viral infections in human hematopoietic cells.

Expression profiling of cellular genes was performed using a 10,000 cDNA human gene array in order to identify expression changes following chronic infection of human hematopoietic cells with Kaposi's Sarcoma-associated Virus (KSHV) also known as Human Herpesvirus 8 (HHV8) and Human T cell leukemia virus-1 (HTLV-1). We performed cell-free in vitro infection of primary bone marrow derived CD34+ cells using semi-purified HHV8 and a mature IL-2 dependent T cell line, KIT 225, using highly concentrated viral stocks prepared from an infectious molecular clone of HTLV-1. Thirty days post infection, mRNA was isolated from infected cultures and uninfected controls and submitted for microarray analysis. More than 400 genes were differentially expressed more than two-fold following HHV8 infection of primary bone marrow derived CD34+ cells. Of these 400, interferon regulatory factor 4 (IRF4), cyclin B2, TBP-associated factor, eukaryotic elongation factor and pim 2 were up-regulated more than 3.5 fold. In contrast, less than 100 genes were differentially expressed more than two-fold following chronic infection of a mature T cell line with HTLV-1. Of these, only cdc7 was up-regulated more than 3.5 fold. These data may provide insight into cellular signatures of infection useful for diagnosis of infection as well as potential targets for therapeutic intervention.

Cell Line↗

PubMed2002

Mechanical spectral signatures of malignant disease? A small-sample, comparative study of continuum vs. nano-biomechanical data analyses.

Thin sections from human breast biopsies were employed to perform a differential analysis of the ultrasound spectral responses from invasive ductal carcinoma and normal tissue. A non-destructive testing methodology was employed, yielding the reflection coefficients as function of frequency in the clinical ultrasound range. The spectral responses were simulated both in the context of continuum and nano-biomechanics, with the objective of quantifying the physical properties that determine the differences in the spectral signature of normal vs. malignant tissue. The properties that were employed for the theoretical reconstruction of the spectra were: the density, the continuum and the nanomechanical elastic constants, and the nanomechanical theory internodal distance. The latter is a measure of the depth-of-penetration of mechanical actions between contiguous tissue elements. Together with vectorial descriptors of the tissue spatial arrangement, the internodal distance variable affords the quantitative incorporation of tissue architectural data in the theoretical model. In this paper, the validity of the nanomechanical approach to tissue characterization is discussed, and its potential extensions to biomolecular marker-based cancer diagnostics and therapeutics are considered.

Breast Neoplasms↗

PubMed2005

Oligomerization of Sulfolobus solfataricus signature amidase is promoted by acidic pH and high temperature.

The recombinant amidase from the hyperthermophylic archaeon Sulfolobus solfataricus (SSAM) a signature amidase, was cloned, purified and characterized. The enzyme is active on a large number of aliphatic and aromatic amides over the temperature range 60-95 degrees C and at pH values between 4.0 and 9.5, with an optimum at pH 5.0. The recombinant enzyme is in the form of a dimer of about 110 kD that reversibly associates into an octamer in a pH-dependent reaction. The pH dependence of the state of association was studied using gel permeation chromatography, analytical ultracentrifugation and dynamic light scattering techniques. At pH 7.0 all three techniques show the presence of two species, in about equal amounts, which is compatible with the existence of a dimeric and an octameric form. In decreasing pH, the dimers formed the octameric species and in increasing pH, the octameric species was converted to dimers. Above pH 8.0, only dimers were present, below pH 3.0 only octamers were present. The association of dimers into octamers decreased in non-polar solvents and increased with temperature. A mutant (Y41C) was obtained that did not show this behavior.

Amides↗

PubMed2006

Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays.

BACKGROUND AND AIMS: Recent cDNA expression profiling analyses indicate that within specific organ cancers Cytokeratins (CKs) dysregulation may identify subgroups with distinct biological phenotypes. Our objectives in this study were (1) to test whether cytokeratins were also distinct on the protein level, (2) to evaluate these biomarkers in a series of well-characterised CRCs, (3) to apply hierarchical cluster analysis to immunohistochemical data. METHODS: Tissue microarrays (TMA) comprising 468 CRC specimens from 203 patients were constructed to evaluate CK5, CK7, CK8, CK13, CK14, CK16, CK17, CK18, CK19 and CK20. In total, 2919 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups represented by reduced CK8 and CK20 expression, that differed by a shorter patients survival. The evaluation of the specific biomarkers by Kaplan-Meier analysis showed that reduced CK8 expression (p<0.01) was significantly associated with shorter patients' survival, but was not an independent factor correlated with tumour stage (pT), grading (G) and nodal stage (pN). CONCLUSIONS: Reduced coexpression of CK8 and CK20 may indicate an epithelial-mesenchymal transition (EMT) representing an important step in the development of more aggressive CRCs. In addition, multiplex analysis of TMAs together with immunohistochemistry (IHC) supplemented by hierarchical clustering are a useful, promising and very powerful tool for the identification of tumour subgroups with diagnostic and prognostic signatures.

Biomarkers, Tumor↗

PubMed2004

Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer.

To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, beta-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low- and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of beta-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high- and low- risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.

Animals↗

PubMed2004

A gene expression signature associated with metastatic outcome in human leiomyosarcomas.

Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.

Gene Expression Profiling↗

PubMed2004

Gene-environment interaction signatures by quantitative mRNA profiling in exfoliated buccal mucosal cells.

Exfoliated cytologic specimens from mouth (buccal) epithelium may contain viable cells, permitting assay of gene expression for direct and noninvasive measurement of gene-environment interactions, such as for inhalation (e.g., tobacco smoke) exposures. We determined specific mRNA levels in exfoliated buccal cells collected by cytologic brush, using a recently developed RNA-specific real-time quantitative reverse transcription-PCR strategy. In a pilot study, metabolic activity of exfoliated buccal cells was verified by 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium assay in vitro. Transcriptional activity was observed, after timed in vivo exposure to mainstream tobacco smoke resulted in induction of CYP1B1 in serially collected buccal samples from the one subject examined. For a set of 11 subjects, mRNA expression of nine genes encoding carcinogen- and oxidant-metabolizing enzymes qualitatively detected in buccal cells was then shown to correlate with that in laser-microdissected lung from the same individuals (Chi2 = 52.91, P < 0.001). Finally, quantitative real-time reverse transcription-PCR assays for seven target gene (AhR, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, and GSTT1) and three reference gene [glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin, and 36B4] transcripts were performed on buccal specimens from 42 subjects. In multivariate analyses, gender, tobacco smoke exposure, and other factors were associated with the level of expression of CYP1B1, GSTP1, and other transcripts on a gene-specific basis, but substantial interindividual variability in mRNA expression remained unexplained. Within the power limits of this pilot study, gene expression signature was not clearly predictive of lung cancer case or control status. This noninvasive and quantitative method may be incorporated into high-throughput human applications for probing gene-environment interactions associated with cancer.

Acyltransferases↗

PubMed2005

Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer.

Microarray analysis has been shown to improve risk stratification of breast cancer. Breast tumors analyzed by hierarchical clustering of expression patterns of "intrinsic" genes have been reported to subdivide into at least four molecular subtypes that are associated with distinct patient outcomes. Using a supervised method, a 70-gene expression profile has been identified that predicts the later appearance or absence of clinical metastasis in young breast cancer patients. Here, we show that distant metastases display both the same molecular breast cancer subtype as well as the 70-gene prognosis signature as their primary tumors. Our results suggest that the capacity to metastasize is an inherent feature of most breast cancers. Furthermore, our data imply that poor prognosis breast carcinomas classified either by the intrinsic gene set or the 70 prognosis genes represent distinct disease entities that seem sustained throughout the metastatic process.

Breast Neoplasms↗

PubMed2006

Two-dimensional transcriptome profiling: identification of messenger RNA isoform signatures in prostate cancer from archived paraffin-embedded cancer specimens.

The expression of specific mRNA isoforms may uniquely reflect the biological state of a cell because it reflects the integrated outcome of both transcriptional and posttranscriptional regulation. In this study, we constructed a splicing array to examine approximately 1,500 mRNA isoforms from a panel of genes previously implicated in prostate cancer and identified a large number of cell type-specific mRNA isoforms. We also developed a novel "two-dimensional" profiling strategy to simultaneously quantify changes in splicing and transcript abundance; the results revealed extensive covariation between transcription and splicing in prostate cancer cells. Taking advantage of the ability of our technology to analyze RNA from formalin-fixed, paraffin-embedded tissues, we derived a specific set of mRNA isoform biomarkers for prostate cancer using independent panels of tissue samples for feature selection and cross-analysis. A number of cancer-specific splicing switch events were further validated by laser capture microdissection. Quantitative changes in transcription/RNA stability and qualitative differences in splicing ratio may thus be combined to characterize tumorigenic programs and signature mRNA isoforms may serve as unique biomarkers for tumor diagnosis and prognosis.

Aged↗