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PubMed2003

Molecular biologic comparison of new bone formation and resorption on microrough and smooth bioactive glass microspheres.

In a recent in vitro study, chemical microroughening of a bioactive glass surface was shown to enhance attachment of MG-63 osteoblastic cells to glass. The current study was designed to delineate the effects of microroughening on the gene expression patterns of bone markers during osteogenesis and new bone remodeling on bioactive glass surface in vivo. With the use of a rat model of paired comparison, a portion of the medullary canal in the proximal tibia was evacuated through cortical windows and filled with microroughened or smooth bioactive glass microspheres. The primary bone-healing response and subsequent remodeling were analyzed at 1, 2, and 8 weeks, respectively, by radiography, pQCT, histomorphometry, BEI-SEM, and molecular biologic analyses. The expression of various genes for bone matrix components (type I collagen, osteocalcin, osteopontin, osteonectin) and proteolytic enzymes (cathepsin K, MMP-9) were determined by Northern analysis of the respective mRNAs. Paired comparison showed significant differences in the mRNAs levels for specific bone matrix components at 2 weeks: osteopontin was significantly higher (p =.01) and osteonectin significantly lower (p =.05) in bones filled with microroughened microspheres than in those filled with smooth microspheres. Bones filled with microrough microspheres also showed significantly increased ratios of cathepsin K and MMP-9 (both markers of osteoclastic resorption) to type I collagen (p =.02 and p =.02, respectively) at 2 weeks and a significantly increased expression of MMP-9 at 8 weeks (p =.05). The pQCT, histomorphometric, and BEI-SEM analyses revealed no significant differences in the pattern of bone-healing response. Based on these results, microroughening of a bioactive glass surface could trigger temporal changes in the expression of specific genes especially by promoting the resorption part of new bone-remodeling processes. Future studies are needed to evaluate if the observed changes of gene expression are directly related to the microrough surface of any biomaterial or are biomaterial specific.

Animals↗
PubMed2007

Expression of somatic DNA repair genes in human testes.

Meiosis is the key process for recombination and reduction of the diploid chromosome set to a haploid one. Many genes that have been found in yeast or mouse models to play a role in meiosis are also important for the repair of DNA damage in somatic cells. To study the DNA repair gene transcriptome during male germ cell development, we have developed a specialized cDNA microarray with 181 human genes which are involved in different somatic DNA repair pathways and/or cell cycle control and 45 control house-keeping genes. This DNA repair gene chip was used to quantify the mRNA expression levels in three human testes samples versus a fibroblast RNA pool. Two hundred twenty genes on the chip (including house-keeping genes) showed detectable expression levels in adult testes. Sixty-four DNA repair- and cell cycle-associated genes showed higher expression levels in testicular cells than in mitotically dividing fibroblasts and, therefore, are likely to be implicated in meiosis. The microarray results of 17 genes with increased expression levels were validated with reverse Northern blots or real-time quantitative RT PCR. Systematic analyses of the meiotic DNA repair gene transcriptome may provide new insights into the genetics of male (in)fertility.

Biomarkers↗
PubMed2005

Oligodendrocyte development and myelination in GFP-transgenic zebrafish.

Green fluorescent protein (GFP) transgenic zebrafish technology has been employed to directly visualize and analyze dynamic developmental processes, such as cell migration and morphogenesis. Stable transgenic zebrafish that express GFP in oligodendrocytes can be a valuable tool to visualize complex myelination processes in vivo, as well as to conduct rapid mutagenesis screens for defective myelination mutants. We investigated whether two myelin gene promoters, the zebrafish P0 promoter and the mouse proteolipid protein (PLP) promoter, drive GFP expression in zebrafish oligodendrocytes. Transiently, both promoters drive enhanced GFP (EGFP) expression in morphologically identifiable oligodendrocytes, premyelinating oligodendrocytes, and possible oligodendrocyte precursors. We have established a stable transgenic zebrafish line, tg(plp:EGFP) zebrafish, at the F1 generation, which expresses enhanced GFP (EGFP) driven by the mouse PLP promoter. In this transgenic line, EGFP-expressing cells are visually detectable around 24-hr postfertilization (hpf), and later at 54 hpf, these cells start exhibiting the clear morphologic characteristics of oligodendrocytes. Shortly afterward, EGFP-expressing oligodendrocytes establish a ventral dominant distribution pattern throughout the central nervous system. This transgenic zebrafish line is likely to serve as a useful tool, in which normal myelination as well as abnormal myelination can be recorded under time-lapse confocal microscopy. Furthermore, it has the potential to greatly facilitate mutagenesis screening for novel dysmyelinating mutants.

Animals↗
PubMed2006

Overexpression and elevated serum levels of phosphoglycerate kinase 1 in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with a very low 5-year survival rate. Currently, there are no valid markers for early detection and targets for therapy. Here, we used 2-DE to analyze the protein profiles of eight PDAC specimens and paired adjacent nontumor tissues. MS was used to identify 15 protein spots that were found to be overexpressed in PDAC tissues versus adjacent controls. One of them was identified as phosphoglycerate kinase (PGK) 1, a secretable glycolytic enzyme known to participate in angiogenesis. Immunohistochemical analysis of 63 PDAC specimens revealed moderate to strong expression of PGK1 in >70% of the tumors. Further Western blotting analysis of cells from tumor and adjacent nontumor tissues obtained by laser capture microdissection confirmed the enhanced expression of PGK1 in tumor cells. Furthermore, the serum levels of PGK1 were significantly higher in PDAC patients (n = 21) than in the control group (n = 25) (p < 0.005), as determined by ELISA. These observations indicate that protein profile analysis using a combination of 2-DE and MS provides an effective strategy for identifying biomarkers that may have diagnostic potential for PDAC, and identify PGK1 as a potential biomarker and/or therapeutic target for PDAC.

Adenocarcinoma↗
PubMed2005

Brain injury and proteomics/peptidomics: is it relevant? an overview.

Proteomics and peptidomics are different and supplemental to genomics, since in contrast to the basically constant genome - the proteome and peptidome are dynamic, constantly changing, and complex networks. Proteomics is traditionally linked to 2D-gel electrophoresis techniques. Concerning peptidomics, three different approaches are currently available, all using mass spectrometry as a key element. The use of proteomics or peptidomics in traumatic brain injury (TBI) research is demanding. From the technical point of view there are high-level requirements concerning the preanalytical phase, specific machinery, sophisticated software and skilled manpower/intellectual input. There are currently no bedside techniques and most methods are suitable for experimental TBI research in specialized laboratories. In screening experiments of CSF following controlled cortical impact in rats we identified several peptides, which, although previously known, were so far not reported in the TBI context or in CSF. Peptidomics and proteomics, as highly complex screening technologies, thus seem to carry a large potential to lead TBI science. Newly "discovered" peptide targets have to be validated with different methodology to establish a real diagnostic or therapeutic value.

Animals↗
PubMed2005

Consistent across-tissue signatures of differential gene expression in Crohn's disease.

An approach based on analysis of variance was applied to raw expression data on 44,760 transcripts in order to identify those with significant differential expression across ileum and colon in Crohn's disease (CD) and ulcerative colitis (UC). The design treated tissue as a block effect, thereby removing this effect statistically and increasing the power to test for effects of disease states (control, CD, and UC). A significant F-statistic for the disease effect was not correlated with the ratios CD/control or UC/control, evidently because many transcripts with high-expression ratios to the control showed inconsistent patterns across tissues. Of 1,053 transcripts showing a significant effect of disease state at the 1% level by the bootstrap test, 508 showed significant difference at the 1% level in a post hoc test for difference between the mean scores for CD and control. These included a number of genes relevant to the mechanism of pathogenesis of CD and a number of genes mapping to genomic regions that have previously shown linkage to CD in association studies.

Analysis of Variance↗
PubMed2003

Circulating angiogenic growth factor levels in mice bearing human tumors using Luminex Multiplex technology.

Tumor angiogenesis is essential for tumor growth and metastasis formation. Luminex methodology was used to measure the levels of four angiogenic cytokines in cell culture medium and in the plasma of mice bearing human tumors. We obtained plasma and conditioned culture medium from 12 different human tumor cell lines. Tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta) were determined by the Luminex FlowMetrix assay. VEGF, TNF-alpha, and bFGF were undetectable in non-tumor-bearing animals. HS746T gastric cancer and Caki-1 renal cell cancer cells in culture produced high levels of VEGF (1000 and 450 pg/10(6) cells, respectively). High levels of TGF-beta were produced by HS746T gastric carcinoma and Calu-6 non-small-cell lung carcinoma (3000 and 1000 pg/10(6) cells, respectively). Caki-1 renal cell carcinoma and Calu-6 non-small-cell lung carcinoma cells in culture produced high levels of bFGF (42 and 10 pg/10(6) cells, respectively). Caki-1, SW2 SCLC, HCT-116 and HT-29 colon tumors produced high plasma levels of VEGF (200, 220, 42, and 151 pg/ml, respectively) and TGF-beta (31, 36, 45, 32 pg/ml, respectively). A positive linear correlation was seen between tumor volume and VEGF in SW2 (r=0.87) and Caki-1 (r=0.47) tumors, and a moderate correlation in HCT116 tumors (r=0.3). Angiogenic profiles in the plasma of nude mice bearing human tumors may be useful to identify appropriate biomarkers for antiangiogenic therapy, as diagnostic and prognostic tools, and to monitor the responses of individual tumors to antiangiogenic therapy.

Angiogenesis Inducing Agents↗
PubMed2006

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers.

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. Tmax occurred between 0.5-3.0 hours with a relatively short plasma half-life of 1-3 h. The coefficient of variation of exposures within a dose level ranged from 22-71% (AUC) to 16-63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438's action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.

Adult↗
PubMed2006

Genomic screening of head and neck cancer and its implications for therapy planning.

Despite great technical improvements in radiotherapy and surgery, survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has still not improved significantly over the last decades. Management of SCCHN has mainly been based on the TNM staging and site over this time period, even though we know that there are individual differences independent of the TNM status. Individual patients with small tumors might have a poor outcome, and patients with large tumors may end up with a favorable prognosis, despite their respective TNM classification. Recent molecular studies indicate that underlying genetic abnormalities may reflect such individual differences independently of TNM status. Individualization of treatment based on such biological properties of the tumors might result in less over as well as under treatment. However, the optimal panel of biomarkers to be used for the individualization of treatment is yet to be defined. A variety of laboratory techniques have been used in studies that investigate the individual biological features, spanning from methods that screen the genome for chromosomal and genetic abnormalities, e.g., cytogenetics, CGH, SKY and cDNA micro array, to detailed studies of specific aberrations. The purpose of this review of the literature is to summarize what has been studied so far by methods for genetic screening and to relate these results to the prediction of the clinical outcome. We conclude that it is time to focus future prospective studies on how treatment can be individualized based on biomarkers in combination with the macroscopic features of SCCHN.

Biomarkers, Tumor↗
PubMed2005

Detecting common gene expression patterns in multiple cancer outcome entities.

Most oncological microarray studies focus on molecular distinctions in different cancer entities. Recently, researchers started using microarrays for investigating molecular commonalities of multiple cancer types. This poses novel bioinformatics challenges. In this paper we describe a method that detects common molecular mechanisms in different cancer entities. The method extends previously described concepts by introducing Meta-Analysis Pattern Matches. In an analysis of four prognostic cancer studies, involving breast cancer, leukemia, and mesothelioma, we are able to identify 42 genes that show consistent up- or down-regulation in patients with a poor disease outcome. These genes complement the set of previously published candidates for universal prognostic markers in cancer.

Algorithms↗
PubMed2006

Screening for motility-associated genes in malignant astrocytoma cell lines.

The most characteristic feature of a malignant astrocytoma is its early and extensive infiltration into adjacent parenchymal structures. We focused on detecting the possible expression changes as the determining factors for malignant astrocytoma's motile ability. We confirmed that four of 39 genes showed different expression on DD-PCR by RT-PCR and Northern blot analysis. These findings suggest that the genes identified may be important for determining high motility in astrocytoma cell lines. These findings may help us understand the molecular invasion mechanism in astrocytomas.

Astrocytoma↗
PubMed2005

Pharmacokinetics and pharmacodynamics of PEGylated IFN-beta 1a following subcutaneous administration in monkeys.

PURPOSE: To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)-beta la following subcutaneous (SC) administration in monkeys. METHODS: Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN-beta 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN-beta PD, were measured at various time-points after dosing. PK/PD profiles were described by noncompartmental methods and pooled data by an integrated mathematical model, where fixed and delayed concentration-time profiles were used as driving functions in an indirect stimulatory response model. RESULTS: PEG-IFN-beta 1a was rapidly absorbed, with peak concentrations observed at about 4-5 h. Compared to previous identical SC doses of IFN-beta la, administration of 1 and 3 MIU/kg of pegylated drug resulted in 27- and 16-fold increases in area under the concentration-time curves. Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well-described by the PK/PD model, and the neopterin elimination rate (0.0190 h(-1)) is consistent with previous estimates. CONCLUSIONS: The PEG-modification of IFN-beta la provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.

2',5'-Oligoadenylate Synthetase↗
PubMed2005

Transcriptional signatures of environmentally relevant exposures in normal human mammary epithelial cells: benzo[a]pyrene.

Changes in gene expression in a panel of primary normal human mammary epithelial cell strains, developed from healthy breast tissue obtained at reduction mammoplasty from different donors, in response to benzo[a]pyrene exposure have been investigated. It was expected that both gene expression changes common to cell strains derived from different donors as well as inter-individual variation would be observed. Therefore, the strategy that has been adopted is to identify potentially important changes, or useful changes from a biomonitoring perspective, using gene-array technology and a small number of donors; then investigate selected transcription responses using a large number of tissue donors and a cheaper method of transcript detection (real-time polymerase chain reaction). Here we report results from four primary normal human mammary epithelial cell strains that were treated with benzo[a]pyrene in vitro for either 6 or 24 h. Transcription was monitored using high-density oligonucleotide arrays (Affymetrix HuGeneFL). Total RNA was used for the preparation of labeled targets that were hybridized to microarrays containing probes representing more than 6800 human genes and expressed sequence tags. Gene expression data were analyzed using the GeneChip software (MAS 5.0). Altered gene expression patterns were observed in response to benzo[a]pyrene in human mammary epithelial cell strains from different donors. Specifically, the dioxin inducible cytochrome P450 CYP1B1 was consistently induced in response to 6 and 24 h exposure to benzo[a]pyrene in cell strains from all four donors. Two other genes that were relatively consistently induced were IL1beta and MMP1. Less consistent changes in other metabolism genes (CYP1A1, CYP11B2, and NQO1) and certain cell cycle control genes GOS2 and AF1Q were also induced, while EGR1 was suppressed. Although no change in p53 transcription was observed, an accumulation of p53 protein was detected using antibodies. A similar accumulation of Waf1 (p21) was also observed using immunohistochemistry, this was expected since p53 is p21's transcription factor. Significant inter-individual variations in both the levels and patterns of gene expression were observed, in response to benzo[a]pyrene exposure. These studies provide a complementary approach to molecular epidemiology for the investigation of differential susceptibility to chemical carcinogens, and specifically polycyclic aromatic hydrocarbons.

Air Pollutants↗
PubMed2006

Data analysis of alternative splicing microarrays.

The importance of alternative splicing in drug and biomarker discovery is best understood through several example genes. For most genes, the identification, detection and particularly quantification of isoforms in different tissues and conditions remain to be carried out. As a result, the focus in drug and biomarker development is increasingly on high-throughput studies of alternative splicing. Initial strategies for the parallel analysis of alternative splicing by microarrays have been recently published. The design specificities and goals of alternative splicing microarrays, in terms of identification and quantification of multiple mRNAs from one gene, are promoting the development of novel methods of analysis.

Algorithms↗
PubMed2006

Molecular pathology of breast apocrine carcinomas: a protein expression signature specific for benign apocrine metaplasia.

Breast cancer is a heterogeneous disease that encompasses a wide range of histopathological types including: invasive ductal carcinoma, lobular carcinoma, medullary carcinoma, mucinous carcinoma, tubular carcinoma, and apocrine carcinoma among others. Pure apocrine carcinomas represent about 0.5% of all invasive breast cancers according to the Danish Breast Cancer Cooperative Group Registry, and despite the fact that they are morphologically distinct from other breast lesions, there are at present no standard molecular criteria available for their diagnosis. In addition, the relationship between benign apocrine changes and breast carcinoma is unclear and has been a matter of discussion for many years. Recent proteome expression profiling studies of breast apocrine macrocysts, normal breast tissue, and breast tumours have identified specific apocrine biomarkers [15-hydroxyprostaglandin dehydrogenase (15-PGDH) and hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase)] present in early and advanced apocrine lesions. These biomarkers in combination with proteins found to be characteristically upregulated in pure apocrine carcinomas (psoriasin, S100A9, and p53) provide a protein expression signature distinctive for benign apocrine metaplasias and apocrine cystic lesions. These studies have also presented compelling evidence for a direct link, through the expression of the prostaglandin degrading enzyme 15-PGDH, between early apocrine lesions and pure apocrine carcinomas. Moreover, specific antibodies against the components of the expression signature have identified precursor lesions in the linear histological progression to apocrine carcinoma. Finally, the identification of proteins that characterize the early stages of mammary apocrine differentiation such as 15-PGDH, HMG-CoA reductase, and cyclooxygenase 2 (COX-2) has opened a window of opportunity for pharmacological intervention, not only in a therapeutic manner but also in a chemopreventive setting. Here we review published and recent results in the context of the current state of research on breast apocrine cancer.

Apocrine Glands↗
PubMed2006

Cloning and expression analysis of an ovine PAP-like protein cDNA, a gene differentially expressed in scrapie.

In a previous study, the mRNA level of a pancreatitis-associated protein (PAP)-like protein was found to be elevated in the ileal Peyer's patch of lambs during the early phase of scrapie infection. Here, we report the isolation of the ovine PAP-like protein cDNA which encodes a putative 178 amino acid protein with a signal peptide and a C-lectin binding domain. Comparisons of REG/PAP proteins between various species showed that the deduced amino acid sequences were conserved. The overall amino acid identity between the ovine PAP-like protein and bovine, human and rat REG/PAP proteins varied from 23% to 85%. In Northern blot analysis the expression of the ovine PAP-like protein mRNA was restricted to the ileal and jejunal Peyer's patches. The cellular expression of the PAP-like protein mRNA in the ovine intestine was further characterized by in situ hybridization. PAP-like protein mRNA was detected in cells of the epithelial lining in most crypts and in some intestinal villi in the ileum and jejunum while in the colon and rectum, the PAP-like protein mRNA expression was only detected in the deep portion of a few crypts. The data provided will offer the possibility to search for a link between this PAP-like protein and early events in the development of scrapie.

Animals↗
PubMed2004

Induction of comprehensible models for gene expression datasets by subgroup discovery methodology.

Finding disease markers (classifiers) from gene expression data by machine learning algorithms is characterized by a high risk of overfitting the data due the abundance of attributes (simultaneously measured gene expression values) and shortage of available examples (observations). To avoid this pitfall and achieve predictor robustness, state-of-the-art approaches construct complex classifiers that combine relatively weak contributions of up to thousands of genes (attributes) to classify a disease. The complexity of such classifiers limits their transparency and consequently the biological insights they can provide. The goal of this study is to apply to this domain the methodology of constructing simple yet robust logic-based classifiers amenable to direct expert interpretation. On two well-known, publicly available gene expression classification problems, the paper shows the feasibility of this approach, employing a recently developed subgroup discovery methodology. Some of the discovered classifiers allow for novel biological interpretations.

Algorithms↗