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  • DKFZ Publication Database  (2,178)
  • IN-VIVO  (1,190)
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  • DKFZ Publication Database  (2,178)
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  • 1
    Keywords: EXPRESSION ; IN-VIVO ; GENE ; transcription ; METABOLISM ; MICE ; NUCLEAR RECEPTORS ; LIVER RECEPTOR HOMOLOG-1 ; LRH-1 ; LIVER-RECEPTOR-HOMOLOG-1
    Abstract: Reverse cholesterol transport (RCT) is an antiatherogenic process in which excessive cholesterol from peripheral tissues is transported to the liver and finally excreted from the body via the bile. The nuclear receptor liver receptor homolog 1 (LRH-1) drives expression of genes regulating RCT, and its activity can be modified by different posttranslational modifications. Here, we show that atherosclerosis-prone mice carrying a mutation that abolishes SUMOylation of LRH-1 on K289R develop less aortic plaques than control littermates when exposed to a high-cholesterol diet. The mechanism underlying this atheroprotection involves an increase in RCT and its associated hepatic genes and is secondary to a compromised interaction of LRH-1 K289R with the corepressor prospero homeobox protein 1 (PROX1). Our study reveals that the SUMOylation status of a single nuclear receptor lysine residue can impact the development of a complex metabolic disease such as atherosclerosis.
    Type of Publication: Journal article published
    PubMed ID: 25176150
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  • 2
    Keywords: IN-VIVO ; MAMMALIAN-CELLS ; LIVING CELLS ; EMBRYONIC STEM-CELLS ; LYSINE-9 METHYLATION ; HP1 PROTEINS ; DNA-METHYLATION ; HISTONE H3 ; CHROMATIN-REMODELING COMPLEXES ; NUCLEOSOME MODIFICATION
    Abstract: The cell establishes heritable patterns of active and silenced chromatin via interacting factors that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts. We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2 demarcate the PCH state. From the experimental data, we developed a predictive mathematical model that explains how chromatin-bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics. This "nucleation and looping" mechanism is particularly robust toward transient perturbations and stably maintains the PCH state. These features make it an attractive model for establishing functional epigenetic domains throughout the genome based on the localized immobilization of chromatin-modifying enzymes.
    Type of Publication: Journal article published
    PubMed ID: 25134515
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  • 3
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; LUNG-CANCER ; ACTIVATION ; RADIATION-THERAPY ; chemotherapy ; SQUAMOUS-CELL CARCINOMA ; CISPLATIN ; tumor microenvironment ; HIF-1 ; GLUCOSE-METABOLISM ; UNFAVORABLE PROGNOSIS ; HUMAN TUMOR XENOGRAFT ; HIF-1-ALPHA ; Local tumor control ; Fractionated radiation ; HIF pathway inhibition ; INDUCIBLE FACTOR-1-ALPHA
    Abstract: BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy. METHODS: When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations. RESULTS: BAY-87-2243 markedly decreased nuclear HIF-1alpha expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control. CONCLUSIONS: Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.
    Type of Publication: Journal article published
    PubMed ID: 25234922
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  • 4
    Keywords: PROTEOMICS ; molecular ; chemosensitivity ; VOLUME ; imaging ; MODELS ; MODEL ; IN-VIVO ; SERIES ; REGULATOR
    Type of Publication: Book chapter
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  • 5
    Keywords: - ; comparison ; UPSTREAM ; microbiology ; ENGLAND ; technique ; computational biology ; methods ; DNA-MICROARRAY ; GO ; INTERFERENCE ; SCALE ; RNA INTERFERENCE ; EXTENSION ; RE ; FEATURES ; signaling ; German ; in combination ; FALSE DISCOVERY RATE ; SIGNALING NETWORK ; signaling networks ; biotechnology ; RNA ; microarray ; GENES ; DNA ; GENE ; GENE-EXPRESSION ; NETWORK ; NETWORKS ; CELL ; Germany ; CELLS ; EXPRESSION ; CANCER CELLS ; CANCER ; PATHWAYS ; MODEL ; MODELS ; PATHWAY ; human ; COMBINATION ; STABILITY ; bioinformatics ; CANCER-CELLS ; SIGNALING PATHWAYS ; SIGNALING PATHWAY ; EFFICIENT ; RECONSTRUCTION ; BIOLOGY ; INTERVENTION ; BREAST ; breast cancer ; BREAST-CANCER ; gene expression ; MICROARRAY DATA
    Type of Publication: Book chapter
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  • 6
    Keywords: CANCER DIAGNOSIS ; THERAPIES ; DNA repair ; methods ; NEW-YORK ; GENE ; GENES ; PATIENT ; CANCER ; CELL ; carcinoma ; radiotherapy ; DIAGNOSIS ; THERAPY ; cell cycle ; CELL-CYCLE ; prognosis ; BREAST ; breast cancer ; BREAST-CANCER ; CANCER-PATIENTS ; side effects ; CANCER PATIENTS
    Type of Publication: Book chapter
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  • 7
    Keywords: IN-VITRO ; IN-VIVO ; VITRO ; VIVO ; review ; TUMORIGENESIS ; PREVENTS ; in vitro
    Type of Publication: Journal article epub ahead of print
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  • 8
    Keywords: treatment ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; SKIN ; mechanisms ; prevention ; HEALTH ; PROMOTER ; BREAST ; breast cancer ; BREAST-CANCER ; cancer prevention ; smoking ; SNP ; REPAIR ; WOMEN ; LYMPHOCYTES ; DAMAGE ; GENOTYPES ; cancer risk ; CANCER-PATIENTS ; INDIVIDUALS ; case-control studies ; DNA-DAMAGE ; CANCER PATIENTS ; SUSCEPTIBILITY GENE ; BODY ; RISK ; GENE ; ENZYMES ; DISEASE ; lung cancer ; LUNG-CANCER ; PATIENT ; MECHANISM ; DNA ; TUMORS ; validation ; DRUG ; RNA ; GENES ; THERAPY ; VITRO ; LUNG ; COMBINATION ; CANCER ; EXPRESSION ; IN-VITRO ; CELLS ; CELL ; tumor ; AGENTS ; radiotherapy ; NSCLC ; CANCER-RISK ; cancer research ; RNA EXPRESSION ; ENZYME ; case control studies ; analysis ; GENOTYPE ; PROFILES ; single-nucleotide ; development ; PROMOTER POLYMORPHISM ; XRCC1 ; VARIANT ; WEIGHT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; case-control study ; GEMCITABINE ; CAPACITY ; DEFICIENCY ; small cell lung cancer ; AGENT ; SINGLE ; DNA repair ; MPO ; APE1
    Abstract: Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case-control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Inter-individual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger beneficial effects were seen in non-small cell lung cancer (NSCLC) patients following gemcitabine and in SCLC patients following etoposide-based treatment. Several DNA repair parameters (polymorphisms, RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before radiotherapy and correlated with the occurrence of acute side effects (radio-hypersensitivity). Our initial analysis of several repair gene variants in breast cancer patients (n = 446) who received radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect cancer risk and therapy outcome. Predisposition to hereditary cancer syndromes is dominated by the strong effects of some high-penetrance tumor susceptibility genes, while predisposition to sporadic cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large population-based studies and validation of the results will be required.
    Type of Publication: Book chapter
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  • 9
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    Wiley VCH
    Keywords: GENES ; TUMORS ; GENE ; tumor
    Type of Publication: Book chapter
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  • 10
    Keywords: MM3 ; therapeutic ; TEMPERATURE ; ACCURATE ; intensity ; HIGH-RESOLUTION ; ultrasound ; GUIDANCE ; MAGNETIC-RESONANCE ; sensitivity ; PERFORMANCE ; PROBE ; VIVO ; IN-VIVO ; tumor ; treatment ; MR ; MRI ; TUMORS ; RESOLUTION
    Abstract: High intensity contact ultrasound (HICU) under MRI guidance may provide minimally invasive treatment of endocavitary digestive tumors (colon/rectum). In this study, opposed-solenoid receiver-only coils were integrated into an endoscopic phased array ultrasound probe to offer high resolution MRI guidance of thermotherapy. The improvement of the image quality and temperature monitoring and control using this device has been investigated in- vivo, on a clinical 1.5T. The comparison endocavitary/external standard coils (voxel: 0.88 x 0.88 x 8 mm3) showed a sensitivity gain up to a factor 4, at the limit of the cooling balloon. Infra-millimeter resolution became feasible for fast MR thermometry while providing an excellent SDT. The endoscopic device was actively operated under automatic temperature control, demonstrating accurate performance.
    Type of Publication: Proceeding
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  • 11
    Keywords: SPECTROSCOPY ; MAGNETIC-RESONANCE ; FREQUENCIES ; PARAMETERS ; IDENTIFICATION ; NMR ; NMR-SPECTROSCOPY ; MODULATION ; WHOLE-BODY ; SPECTRA ; CANCER ; IN-VIVO ; VIVO ; MR ; RESOLUTION ; TIME ; cancer research ; glutamine ; WELL ; TIMES ; 3
    Abstract: Previously, it has been shown that glutamate can be distinguished from glutamine when their zero-quantum coherence (ZQC) modulation frequencies as well as their chemical shift values are used as identification parameters in 2D spectra. However, acquisition times for such spectra exceeded four hours. We now show that by recording 2D spectra, which are undersampled along the ZCQ modulation frequency axis and then applying a Fourier Shift, glutamate can be distinguished from glutamine in 50 minutes. We demonstrate this on a healthy volunteer using a 3 Tesla whole-body MR tomograph and show that there is no loss in resolution.
    Type of Publication: Proceeding
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  • 12
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    Taylor & Francis Group CRC Pre
    Keywords: PHASE ; TECHNOLOGY ; technique ; DRUG DEVELOPMENT ; clinical studies ; in vivo ; EXTENT ; COMPOUND ; CLINICAL-APPLICATION ; pharmaceutical industry ; STEM ; DISORDERS ; development ; DRUG DISCOVERY ; INCREASE ; DISEASE ; DISEASES ; INFORMATION ; imaging ; validation ; RESOLUTION ; DRUG ; ARTHRITIS ; CANCER ; IN-VIVO ; THERAPY ; VIVO ; MR ; MRI ; TRANSPLANTATION ; INTERVENTION ; DISCOVERY ; MAGNETIC-RESONANCE ; TARGET ; IDENTIFICATION ; STAGE
    Abstract: Imaging technologies are receiving much attention in the pharmaceutical industry because of their potential for accelerating drug discovery and development. Magnetic Resonance (MR) Imaging is one of the principal modalities since it allows anatomical, functional, metabolic, and to a certain extent even target-related information to be gathered in vivo at high resolution, favouring the characterization of a disease state and the corresponding drug intervention. The non-invasiveness of MR strengthens the link between preclinical and clinical pharmaceutical research, contributing to improve the characterization of compound effects in early stages of the discovery process in order to increase the chances of success in later phases of drug development. Edited by a leading researcher in MR technology, with contributions from foremost experts in academia and the pharmaceutical industry, this title illustrates the use of MR techniques throughout the drug discovery and development process, from target identification and validation to clinical studies. Numerous chapters focus on individual disease areas, including neurological, cardiac, and pulmonary disorders, cancer studies, diabetes, arthritis, solid organ transplantation, and stem cell-based therapies, showing that different imaging solutions are needed for specific organs
    Type of Publication: Book chapter
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  • 13
  • 14
    Keywords: human brain ; in vivo ; imaging ; brain ; human ; IN-VIVO ; VIVO
    Type of Publication: Book chapter
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  • 15
    Keywords: gene transfer ; GENE-TRANSFER ; GENE-EXPRESSION ; TUMORS ; GENE ; EXPRESSION ; tumor ; IN-VIVO ; imaging ; molecular imaging ; gene expression ; BIOLOGY ; TRACER ; MALIGNANT-TUMORS ; molecular ; PHAGE DISPLAY ; PHAGE
    Type of Publication: Book chapter
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  • 16
    Keywords: ESTROGEN ; estrogen receptor ; in vivo ; THERAPIES ; ESTROGEN-RECEPTOR ; mechanisms ; DISSECTION ; LIGANDS ; RECEPTOR ; IN-VIVO ; THERAPY ; VIVO ; MECHANISM ; LIGAND
    Type of Publication: Book chapter
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  • 17
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; CANCER ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; ADVANCED SOLID TUMORS ; AGENTS ; ANGIOSTATIN ; BLOOD ; carcinoma ; CELL ; CELL LUNG-CANCER ; CELL-PROLIFERATION ; CLINICAL-TRIAL ; COMBINATION ; DOPPLER ; ENDOTHELIAL GROWTH-FACTOR ; evaluation ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MICROSCOPY ; MICROVESSEL DENSITY ; MODEL ; MODELS ; neoplasms ; PATHWAY ; PATHWAYS ; PERFUSION ; PHASE-I ; PROSTATE ; RECOMBINANT HUMAN ENDOSTATIN ; THERAPY ; TOXICITY ; tumor growth ; TYROSINE KINASE ; VITRO ; VIVO
    Abstract: The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (M), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested
    Type of Publication: Journal article published
    PubMed ID: 14695206
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  • 18
    Keywords: DOPPLER ; Germany ; IN-VIVO ; MODEL ; MODELS ; CT ; VOLUME ; NEW-YORK ; ACCURACY ; computed tomography ; HEART ; INTEROBSERVER VARIABILITY ; PIGS ; RESOLUTION ; SURGERY ; validation
    Abstract: Background. Cardiac functional assessment represents the basis for diagnostics and cardiac operation planning. Spiral computed tomography (CT) combines the advantages of three-dimensional imaging and high temporal resolution when using gating techniques. However, in vivo validation data of this novel imaging technology are lacking. The purpose of this study was to validate in vivo the new imaging method using retrospective gating and to evaluate the clinical usefulness of the achieved temporal resolution. Methods. In domestic pigs (n = 10, weight 35 to 40 kg) a flowmeter was placed surgically on the ascending aorta. Flow velocity integrated over systole served as the gold standard for left ventricular (LV) stroke volume (LVSV-FM). CT signal, projection data, pacemaker signal, and flow velocity were recorded simultaneously at constant heart rate (pacemaker, 90 beats per minute). End-systolic and end-diastolic frames were calculated by retrospective gating. LV volumes were traced, the difference representing CT stroke volume (LVSV-CT). Image data were three-dimensionally reconstructed using ray- tracing. Results. Temporal resolution was 170 ms. Correlation of stroke volumes was high (r = 0.94, mean difference 1.75 mL). Intraobserver (0.49 mL, for LVEDV, 0.31 for LVESV) and interobserver variability (p = 0.21 and p = 0.06, respectively) were low. Postprocessing resulted in four-dimensional beating- heart models useful for operation planning. Conclusions. Spiral CT using retrospective gating was validated in vivo. Clinically acceptable temporal resolution and accuracy in determining cardiac stroke volumes were found. As a true volumetric imaging modality the method may now play an important role in computer- assisted diagnostics and surgery. (C) 2003 by The Society of Thoracic Surgeons
    Type of Publication: Journal article published
    PubMed ID: 12645712
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  • 19
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; tumor ; IN-VIVO ; GENE ; TUMORS ; ACCUMULATION ; CATECHOLAMINES ; gene therapy ; human norepinephrine transporter ; I-123 MIBG ; LINES ; METAIODOBENZYLGUANIDINE UPTAKE ; MIBG uptake ; MICE ; NEUROBLASTOMA-CELLS ; NORADRENALINE TRANSPORTER ; NUCLEAR-MEDICINE ; radiation ; RELEASE ; STORAGE ; TIME ; TRANSDUCTION
    Abstract: The transport of MIBG by the human norepinephrine transporter (hNET) seems to be the critical step in the treatment of MIBG- concentrating tumors. Therefore, we investigated whether the accumulation of MIBG may be induced by retroviral transect on of the hNET gene in Morris hepatoma cells. Methods: A bicistronic retroviral vector for the transfer of the hNET coding sequence and the hygromycin resistance gene was generated. Morris hepatoma cells (MH3924A) were infected with the respective retroviral particles, and hNET-expressing cell lines MHhNEThyg1 to MHhNEThyg9 were obtained through hygromycin selection. The uptake of H-3-norepinephrine or I-131-MIBG and the efflux of I-131-MIBG were determined in transfected and wild-type cells. In addition, the I-131-MIBG distribution was monitored in nude mice and rats bearing wild-type and hNET- expressing hepatomas. Results: hNET-expressing hepatoma cell lines accumulated up to 36 times more norepinephrine than did wild-type cells and 8 times more than did hNET-expressing neuroblastoma cell line SK-N-SH. The addition of nisoxetine, a selective inhibitor of noradrenaline uptake, inhibited norepinephrine uptake. Maximal I-131-MIBG accumulation was observed 2 h after incubation and was followed by 43% efflux within 4 h after the I-131-MIBG-containing medium had been removed. In vivo experiments performed with nude mice bearing both hNET-expressing and wild-type tumors showed a 10-fold- higher accumulation of I-131-MIBG in transfected tumors than in wild-type tumors. The ex vivo calculations revealed doses of 605 and 75 mGy in hNET-expressing and wild-type tumor tissues, respectively. Conclusion: Transduction of the hNET gene enables Morris hepatoma cells to accumulate norepinephrine and MIBG. However, the retention of MIBG is brief; therefore, the absorbed dose of radiation in vivo is not expected to be therapeutically effective
    Type of Publication: Journal article published
    PubMed ID: 12791828
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  • 20
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; PATHWAY ; PATHWAYS ; ACETATE-NONUTILIZING MUTANTS ; CDNA ; CDNA CLONES ; CLONES ; CLONING ; CRASSA ; DISTINCT ; DNA-microarray analysis,transcriptional profiling,correspondence analysis,acetate metabolism,Neurosp ; ENZYMES ; FILAMENTOUS FUNGUS ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; GENOME SEQUENCE ; HYBRIDIZATION ; microarray ; NMT1 ; PROTEIN ; PROTEINS ; RNA ; SACCHAROMYCES-CEREVISIAE ; SAMPLE ; SAMPLES ; transcription
    Abstract: Nutrient-dependent variations in transcript levels of the filamentous fungus Neurospora crassa were studied on a microarray containing some 4700 cDNAs. Cells were grown in minimal and acetate medium. The isolated RNA was analyzed in comparison to the results obtained upon the hybridization of samples prepared from the RNA of cells grown in full medium. Altogether, 160 cDNA clones exhibited significant variations, falling into five distinct subgroups of very similar transcription profiles. This is indicative of the occurrence of a high degree of co-regulation of genes in N. crassa. Especially the regulation of the expression of proteins involved in metabolic pathways was found to be strongly regulated at the RNA level. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14599890
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  • 21
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; IN-VIVO ; MODEL ; DISEASE ; DISTINCT ; MICE ; ACTIVATED MACROPHAGES ; ACTIVATION ; COMPLEX ; CRESCENTIC GLOMERULONEPHRITIS ; INJURIES ; LIGAND ; MESANGIAL CELLS ; MONOCYTE ARREST ; NEPHRITIS ; NITRIC-OXIDE ; RANTES ; RESPONSES
    Abstract: The chemokine CC chemokine ligand (CCL)5/RANTES as well as its respective receptor CCR5 mediate leukocyte infiltration during inflammation and are up-regulated early during the course of glomerulonephritis (GN). We tested the effects of the two CCL5/RANTES blocking analogs, Met-RANTES and amino-oxypentane- RANTES, on the course of horse apoferritin (RAF)induced GN. HAF-injected control mice had proliferative GN with mesangial immune complex deposits of IgG and HAF. Daily i.p. injections of Met-RANTES or amino-oxypentane-RANTES markedly reduced glomerular cell proliferation and glomerular macrophage infiltration, which is usually associated with less glomerular injury and proteinuria in RAF-GN. Surprisingly, however, RAF-GN mice treated with both analogs showed worse disease with mesangiolysis, capillary obstruction, and nephrotic range albuminuria. These findings were associated with an enhancing effect of the CCL5/RANTES analogs on the macrophage activation state, characterized by a distinct morphology and increased inducible NO synthetase expression in vitro and in vivo, but a reduced uptake of apoptotic cells in vivo. The Immoral response and the Th1/Th2 balance in HAF-GN and mesangial cell proliferation in vitro were not affected by the CCL5/RANTES analogs. We conclude that, despite blocking local leukocyte recruitment, chemokine analogs can aggravate some specific disease models, most likely due to interactions with systemic immune reactions, including the removal of apoptotic cells and inducible NO synthetase expression
    Type of Publication: Journal article published
    PubMed ID: 12759447
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  • 22
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VIVO ; LUNG-CANCER ; DNA adducts ; RISK ; GENE ; LINES ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; CYP1A2 ; CYTO-TOXIC METABOLITES ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; GENETIC POLYMORPHISMS ; HETEROCYCLIC AMINES ; HETEROLOGOUS EXPRESSION ; HUMAN CYTOSOLIC SULFOTRANSFERASES ; IONS ; metabolic activation ; NAT : SULT ; nitro-PAH ; P-32- postlabeling ; PHENOL SULFOTRANSFERASES ; POSTLABELING ANALYSIS
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and ambient air pollution. 3-Aminobenzanthrone (3-ABA), 3- acetylaminobenzanthrone (3-Ac-ABA) and N-acetyl-N-hydroxy-3- aminobenzanthrone (N-Ac-N-OH-ABA) have been identified as 3-NBA metabolites. Recently we found that 3-NBA and its metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) form the same DNA adducts in vivo in rats. In order to investigate whether human cytochrome P450 (CYP) enzymes (i.e., CYPIA2), human N,O- acetyltransferases (NATs) and sulfotransferases (SULTs) contribute to the metabolic activation of 3-NBA and its metabolites we developed a panel of Chinese hamster V79MZ-hIA2 derived cell lines expressing human CYPIA2 in conjunction with human NATI, NAT2, SULTIAI or SULTIA2, respectively. Cells were treated with 0.01, 0.1 or I muM 3-NBA, or its metabolites (3- ABA, 3-Ac-ABA and N-Ac-N-OH-ABA). Using both enrichment versions of the P-32-postlabeling assay, nuclease P I digestion and butanol extraction, essentially 4 major and 2 minor DNA adducts were detected in the appropriate cell lines with all 4 compounds. The major ones were identical to those detected in rat tissue; the adducts lack an N-acetyl group. Human CYPIA2 was required for the metabolic activation of 3-ABA and 3-Ac-ABA (probably via N-oxidation) and enhanced the activity of 3-NBA (probably via nitroreduction). The lack of acetylated adducts suggests N-deacetylation of 3-Ac-ABA and N-Ac-N-OH-ABA. Thus, N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be a common intermediate for the formation of the electrophilic arylnitrenium ions capable of reacting with DNA. Human NAT I and NAT2 as well as human SULTIAI and SULTIA2 strongly contributed to the high genotoxicity of 3-NBA and its metabolites. Moreover, N,O-acetyltransfer reactions catalyzed by human NATs leading to the corresponding N-acetoxyester may be important in the bioactivation of N-Ac-N-OH-ABA. As human exposure to 3-NBA is likely to occur primarily via the respiratory tract, expression of CYPs, NATs and SULTs in respiratory tissues may contribute significantly and specifically to the metabolic activation of 3-NBA and its metabolites. Consequently, polymorphisms in these genes could be important determinants of lung cancer risk from 3-NBA
    Type of Publication: Journal article published
    PubMed ID: 12740904
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  • 23
    Keywords: EXPRESSION ; INHIBITOR ; Germany ; KINASE ; GENE ; GENES ; PROTEIN ; SACCHAROMYCES-CEREVISIAE ; transcription ; COMPONENTS ; COMPLEX ; COMPLEXES ; cell cycle ; CELL-CYCLE ; CYCLE ; protein kinase ; PROTEIN-KINASE ; IDENTIFICATION ; gene expression ; protein kinase CK2 ; Saccharomyces cerevisiae ; SUBUNIT ; YEAST ; BUDDING YEAST ; DISRUPTION ; EXPRESSION ANALYSIS ; HOLOENZYME ; PHO pathway
    Abstract: The budding yeast Saccharomyces cerevisiae encounters phosphate starvation by the transcription-regulated PHO pathway. We find that genetic perturbation of protein kinase CK2, a conserved tetrameric Ser/Thr phosphotransferase with links to cell cycle and transcription, affects expression of PHO pathway genes in a subunit- and isoform-specific manner. Remarkably, the genes encoding phosphate supplying phosphatases and transporters are significantly repressed, while the genes encoding components of the central pathway regulator complex, a cyclin-dependent kinase (CDK), a cyclin, and a CDK inhibitor, remain unaltered. Thus, perturbation of CK2 uncouples the executive part of the PHO pathway from its cyclin-CDK control complex. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies
    Type of Publication: Journal article published
    PubMed ID: 12606059
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  • 24
    Keywords: EXPRESSION ; screening ; DISTINCT ; GENE ; GENES ; GENOME ; DNA ; FAMILY ; ASSOCIATION ; autistic disorder,susceptibility gene,chromosome 2,mutation screening,association ; CANDIDATE GENE ; chromosome ; DISORDER ; DLX GENES ; FREQUENCY ; GENOMEWIDE SCREEN ; GENOMIC SCREEN ; GLUTAMIC-ACID DECARBOXYLASE ; LINKAGE ; polymorphism ; POLYMORPHISMS ; SIGNAL ; single nucleotide polymorphism ; SUSCEPTIBILITY ; SUSCEPTIBILITY GENES ; SUSCEPTIBILITY LOCUS ; VARIANTS
    Abstract: The results from several genome scans indicate that chromosome 2q21-q33 is likely to contain an autism susceptibility locus. We studied the potential contribution of nine positional and functional candidate genes: TBR-1; GAD1; DLX1; DLX2; cAMP-GEFII; CHN1; ATF2; HOXD1 and NEUROD1. Screening these genes for DNA variants and association analysis using intragenic single nucleotide polymorphisms did not provide evidence for a major role in the aetiology of autism. Four rare nonsynonymous variants were identified, however, in the cAMP-GEFII gene. These variants were present in five families, where they segregate with the autistic phenotype, and were not observed in control individuals. The significance of these variants is unclear, as their low frequency in IMGSAC families does not account for the relatively strong linkage signal at the 2q locus. Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility
    Type of Publication: Journal article published
    PubMed ID: 14593429
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  • 25
    Keywords: CANCER ; PROTECTION ; MODEL ; DISEASE ; EPIDEMIOLOGY ; HISTORY ; RISK ; GENE ; GENES ; SAMPLE ; FAMILY ; RISK-FACTORS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; BRCA1 ; case-only design ; family history ; gene carrier probability ; LINKAGE ANALYSIS ; mixture logistic model ; ovarian cancer ; OVARIAN-CANCER ; population and sibling controls ; WOMEN
    Abstract: Background The effect of environmental/lifestyle factors on breast cancer risk may be modified by genetic predisposition. Methods In a population-based case-control-family study performed in Germany including 706 cases by age 50 years, 1381 population, and 252 sister controls, we investigated main effects for environmental/lifestyle factors and genetic susceptibility and gene-environment interaction (G x E). Different surrogate measures for genetic predisposition using pedigree information were used: first-degree family history of breast or ovarian cancer; and gene carrier probability using a genetic model based on rare dominant genes. Possible G x E interaction was studied by (1) logistic regression using cases and population controls including an interaction term; (2) comparing results using sister controls and population controls; (3) case-only analysis with logistic regression and (4) a mixture logistic model. Results Familial predisposition showed the strongest main effect and the estimated gene carrier probability gave the best fit. High parity and longer duration of breastfeeding reduced breast cancer risk significantly, a history of abortions increased risk and age at menarche showed no significant effect. We found significant G x E interaction between parity and genetic susceptibility using different surrogate measures. In women most likely to have a high genetic susceptibility, high parity was less protective. Later age at menarche was protective in women with a positive family history. No evidence for G x E interaction was found for breastfeeding and abortion. Conclusions These findings corroborate results from other studies and provide further evidence that the magnitude of protection from parity is reduced in women most likely to have a genetic risk in spite of the limitations of using surrogate genetic measures
    Type of Publication: Journal article published
    PubMed ID: 12690006
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  • 26
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; IN-VIVO ; PATHWAYS ; PROTEIN ; SACCHAROMYCES-CEREVISIAE ; COMPLEX ; COMPLEXES ; BINDING ; IDENTIFICATION ; Saccharomyces cerevisiae ; YEAST ; lifestyle ; BETA ; CONSERVATION ; EGG EXTRACTS ; GTPASE RAN ; IMPORTIN-ALPHA ; LOCALIZATION ; MESSENGER-RNA EXPORT ; NUCLEAR EXPORT RECEPTOR ; NUCLEUS ; TRANSPORT FACTOR ; XENOPUS
    Abstract: The small Ras-like GTPase Ran plays an essential role in the transport of macromolecules in and out of the nucleus and has been implicated in spindle (1, 2) and nuclear envelope formation (3, 4) during mitosis in higher eukaryotes. We identified Saccharomyces cerevisiae open reading frame YGL164c encoding a novel RanGTP-binding protein, termed Yrb30p. The protein competes with yeast RanBP1 (Yrb1p) for binding to the GTP-bound form of yeast Ran (Gsp1p) and is, like Yrb1p, able to form trimeric complexes with RanGTP and some of the karyopherins. In contrast to Yrb1p, Yrb30p does not coactivate but inhibits RanGAP1(Rna1p)-mediated GTP hydrolysis on Ran, like the karyopherins. At steady state, Yrb30p localizes exclusively to the cytoplasm, but the presence of a functional nuclear export signal and the localization of truncated forms of Yrb30p suggest that the protein shuttles between nucleus and cytoplasm and is exported via two alternative pathways, dependent on the nuclear export receptor Xpo1p/Crm1p and on RanGTP binding. Whereas overproduction of the full-length protein and complete deletion of the open reading frame reveal no obvious phenotype, overproduction of C-terminally truncated forms of the protein inhibits yeast vegetative growth. Based on these results and the exclusive conservation of the protein in the fungal kingdom, we hypothesize that Yrb30p represents a novel modulator of the Ran GTPase switch related to fungal lifestyle
    Type of Publication: Journal article published
    PubMed ID: 12578832
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  • 27
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; GENE ; GENE-EXPRESSION ; RNA ; TUMORS ; ACTIVATION ; PROTEIN FAMILY ; INDUCTION ; SUSCEPTIBILITY ; TARGET ; gene expression ; resistance ; HUMAN-TUMORS ; STIMULI ; CANCER-CELLS ; DELIVERY ; MAMMALIAN-CELLS ; SMALL INTERFERING RNAS ; doxorubicin ; HUMAN-TUMOR-CELLS ; IAP PROTEINS ; POSITIVE CANCER-CELLS ; RNA interference,inhibitors of apoptosis,chemotherapy,HeLa,melanoma ; STRATEGIES
    Abstract: Increased resistance to apoptosis is a hallmark of many tumor cells. The functional inhibition of specific antiapoptotic factors may provide a rational basis for the development of novel therapeutic strategies. We investigated here whether the RNA interference (RNAi) technology could be used to increase the apoptotic susceptibility of cancer cells. As a molecular target, we chose the antiapoptotic livin (ML-IAP, KIAP) gene, which is expressed in a subset of human tumors. We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression. Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFalpha. The effects were specific for Livin-expressing tumor cells. Our results (i) provide direct evidence that the intracellular interference with livin gene expression resensitizes human tumor cells to apoptosis, (ii) define the livin gene as a promising molecular target for therapeutic inhibition, and (iii) show that the livin gene is susceptible to efficient and specific silencing by the siRNA technology
    Type of Publication: Journal article published
    PubMed ID: 14614456
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  • 28
    Keywords: CANCER ; IN-VITRO ; tumor ; AGENTS ; Germany ; IN-VIVO ; INHIBITION ; screening ; SYSTEM ; SYSTEMS ; RISK ; ENZYMES ; DRUG ; NITRIC-OXIDE ; murine ; RISK-FACTORS ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; mechanisms ; culture ; IDENTIFICATION ; prevention ; risk factors ; MODULATION ; RISK FACTOR ; butyrate ; HEPATOMA ; fatty acids ; FATTY-ACIDS ; NF-kappa B ; ALCOHOL ; SODIUM-BUTYRATE ; curcumin ; ORNITHINE DECARBOXYLASE ; ANTIOXIDANT ; bioassay systems ; cancer chernoprevention ; CONSTITUENTS ; iNOS ; PEITC ; SULFORAPHANE ; SUPEROXIDE
    Abstract: Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepalclc7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl- radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti- tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short- chain fatty acids (sodium butyrate), indoles (indole-3- carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti- inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628514
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  • 29
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; DISEASE ; NEW-YORK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; cell line ; TISSUE ; validation ; LINES ; MARKER ; TISSUES ; tumour ; CELL-LINES ; BREAST-CANCER ; TARGET ; immunohistochemistry ; gene expression ; affymetrix ; CELL-LINE ; LINE ; MARKERS ; CARCINOMAS ; adenocarcinoma ; OVEREXPRESSION ; PERIPHERAL-BLOOD ; GASTRIC-CANCER ; ADAM9 ; CDNA MICROARRAYS ; cell lines ; expression profiling ; HUMAN GENES ; K-RAS ; METALLOPROTEASE-DISINTEGRIN ; microarray hybridisation ; microdissection ; OLIGONUCLEOTIDE ARRAYS ; pancreatic cancer ; pancreatic carcinoma ; SERIAL ANALYSIS
    Abstract: In a search for new molecular markers of pancreatic ductal adenocarcinoma (PDAC), we compared the gene expression profiles of seven pancreatic carcinomas and one carcinoma of the papilla Vateri with those of duct cells from three non-neoplastic pancreatic tissues. In addition, the human pancreatic duct cell line and five PDAC cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2, HPAF) were examined. RNA was extracted from microdissected tissue or cultured cell lines and analysed using a custom-made Affymetrix Chip containing 3023 genes, of which 1000 were known to be tumour associated. Hierarchical clustering revealed 81 differentially expressed genes. Of all the genes, 26 were downregulated in PDAC and 14 were upregulated in PDAC. In PDAC cell lines versus normal pancreatic duct cells, 21 genes were downregulated and 20 were upregulated. Of these 81 differentially expressed genes, 15 represented human genes previously implicated in the tumourigenesis of PDAC. From the genes that were so far not known to be associated with PDAC tumorigenesis, we selected ADAM9 for further validation because of its distinct overexpression in tumour tissue. Using immunohistochemistry, the over-expressed gene, ADAM9, was present in 70% of the PDACs analysed. In conclusion, using microarray technology we were able to identify a set of genes whose aberrant expression was associated with PDAC and may be used to target the disease
    Type of Publication: Journal article published
    PubMed ID: 12942322
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  • 30
    Keywords: RECEPTOR ; IN-VIVO ; GENE ; PROTEIN ; animals ; PROMOTERS ; MAMMALIAN-CELLS ; COMPLEMENTATION ; LUCIFERASE ; REPORTER GENE-EXPRESSION
    Abstract: Genomic research is expected to generate new types of complex observational data, changing the types of experiments as well as our understanding of biological processes. The investigation and definition of relationships among proteins is essential for understanding the function of each gene and the mechanisms of biological processes that specific genes are involved in. Recently, a study by Paulmurugan et al. demonstrated a tool for in vivo noninvasive imaging of protein-protein interactions and intracellular networks
    Type of Publication: Journal article published
    PubMed ID: 12788540
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  • 31
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; CELL ; human ; IN-VIVO ; VITRO ; VIVO ; NETWORK ; GENE ; PROTEIN ; PROTEINS ; TIME ; INFECTION ; RAT ; CONTRAST ; STAGE ; DISRUPTION ; MUTATION ; MUTATIONS ; MUSCLE ; ASSEMBLY PROPERTIES ; SERIES ; GREEN FLUORESCENT PROTEIN ; ORGANIZATION ; ADENOVIRUS ; ALPHA-B-CRYSTALLIN ; DILATED CARDIOMYOPATHY ; EPIDERMOLYSIS-BULLOSA SIMPLEX ; INTERMEDIATE-FILAMENT PROTEINS ; MICE LACKING DESMIN ; MUSCULAR-DYSTROPHY ; SKELETAL MYOPATHY ; SMOOTH-MUSCLE ; Z-DISCS
    Abstract: Mutations in desmin have been associated with a subset of human myopathies. Symptoms typically appear in the second to third decades of life, but in the most severe cases can manifest themselves earlier. How desmin mutations lead to aberrant muscle function, however, remains poorly defined. We created a series of four mutations in rat desmin and tested their in vitro filament assembly properties. RDM-G, a chimera between desmin and green fluorescent protein, formed protofilament-like structures in vitro. RDM-1 and RDM-2 blocked in vitro assembly at the unit-length filament stage, while RDM-3 had more subtle effects on assembly. When expressed in cultured rat neonatal cardiac myocytes via adenovirus infection, these mutant proteins disrupted the endogenous desmin filament to an extent that correlated with their defects in in vitro assembly properties. Disruption of the desmin network by RDM-1 was also associated with disruption of plectin, myosin, and a-actinin organization in a significant percentage of infected cells. In contrast, expression of RDM-2, which is similar to previously characterized human mutant desmins, took longer to disrupt desmin and plectin organization and had no significant effect on myosin or alpha-actinin organization over the 5-day time course of our studies. RDM-3 had the mildest effect on in vitro assembly and no discernable effect on either desmin, plectin, myosin, or a-actinin organization in vivo. These results indicate that mutations in desmin have both direct and indirect effects on the cytoarchitecture of cardiac myocytes
    Type of Publication: Journal article published
    PubMed ID: 12529857
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  • 32
    Keywords: IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; PATHWAY ; VITRO ; VIVO ; SITE ; PROTEIN ; radiation ; ACTIVATION ; COMPLEX ; COMPLEXES ; DNA ; CARCINOGENESIS ; cell cycle ; CELL-CYCLE ; CYCLE ; PHOSPHORYLATION ; MUTANT ; LESIONS ; PROGRESSION ; CYCLE PROGRESSION ; DAMAGE ; DNA-DAMAGE ; DEGRADATION ; ATR ; CHK1 ; CYCLE CONTROL ; G(1)/S TRANSITION ; PROTEASOME ; S-PHASE ; serine
    Abstract: The human Cdc25A phosphatase plays a pivotal role at the G(1)/S transition by activating cyclin E and A/Cdk2 complexes through dephosphorylation. In response to ionizing radiation, Cdc25A is phosphorylated by both Chk1 and Chk2 on Ser-123. This in turn leads to ubiquitylation and rapid degradation of Cdc25A by the proteasome resulting in cell cycle arrest. We found that in response to UV irradiation, Cdc25A is phosphorylated at a different serine residue, Ser-75. Significantly, Cdc25A mutants carrying alanine instead of either Ser-75 or Ser-123 demonstrate that only Ser-75 mediates protein stabilization in response to UV-induced DNA damage. As a consequence, cyclin E/Cdk2 kinase activity was high. Furthermore, we find that Cdc25A was phosphorylated by Chk1 on Ser-75 in vitro and that the same site was also phosphorylated in vivo. Taken together, these data strongly suggest that phosphorylation of Cdc25A on Ser-75 by Chk1 and its subsequent degradation is required to delay cell cycle progression in response to UV-induced DNA lesions
    Type of Publication: Journal article published
    PubMed ID: 12759351
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  • 33
    Keywords: CANCER ; carcinoma ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; incidence ; liver ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; FAMILY ; primary ; tumour ; MEMBER ; MEMBERS ; ASSOCIATION ; CANDIDATE GENE ; SUSCEPTIBILITY ; AGE ; ovarian cancer ; OVARIAN-CANCER ; CERVICAL-CANCER ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; DATABASE ; SIR ; familial risk ; CARRIERS ; FAMILY-CANCER DATABASE ; bile duct ; BILE-DUCTS ; CHOLECYSTECTOMY ; GALLBLADDER-CANCER ; RELATIVES ; VIRAL-HEPATITIS
    Abstract: Background and aims: Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. Methods: The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961-1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (Cls) were calculated for cancers in family members. Results: All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% Cl 1.05- 2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% Cl 2.07-10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% Cl 1.48-11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% Cl 1.23-4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. Conclusions: This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks
    Type of Publication: Journal article published
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  • 34
    Keywords: CANCER ; Germany ; EPIDEMIOLOGY ; incidence ; RISK ; RISKS ; GENE ; GENES ; SUSCEPTIBILITY ; SUSCEPTIBILITY GENES ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; prevention ; DESIGN ; DIFFERENCE ; AGE ; BRCA1 ; WOMEN ; SWEDEN ; DATABASE ; REGION ; MUTATIONS ; MORPHOLOGY ; SIR ; familial risk ; NATIONWIDE ; FAMILY-CANCER DATABASE ; RELATIVES ; familial risk,half sisters,risk factors,sibling risk ; INTERPRETING FAMILY ; SUSCEPTIBILITY GENE
    Abstract: Purpose. The familial risk of female breast cancer is somewhat less than 2.0 when a first-degree relative is diagnosed with breast cancer, but it is not known to what extent heritable or environmental factors explain the familial clustering. Such data would be valuable for prevention and gene identification strategies.Experimental design. We used the nation-wide Swedish Family-Cancer Database on 10.2 million individuals and 190,000 mothers' and 26,000 daughters' breast cancers to calculate familial standardised incidence ratios (SIRs), for all invasive breast cancers in daughters, who were 0-66 years old. Over 5500 familial breast cancers were recorded.Results. The familial SIR for all invasive breast cancer was 1.71 by breast cancer in the mother only, 1.95 by breast cancer in a sister only, and 2.75 by breast cancer in both a mother and sister. The SIRs did not change when adjustments were done for period, age at first birth, parity, socio-economic status and region. Age difference between sisters showed a small variation in risk for breast cancer but the highest SIR was found for those whose age difference was from 6 to 10 years. Half sisters showed an excess of familial risks exactly half of full sisters, the SIR being 1.44.Conclusions. These data suggest that familial aggregation of breast cancer is mainly due to heritable causes. Because the known susceptibility genes only explain about a quarter of the familial aggregation, the remaining majority offers a challenge to new genomic approaches
    Type of Publication: Journal article published
    PubMed ID: 14672399
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  • 35
    Keywords: BLOOD ; IN-VIVO ; MODEL ; IMAGES ; liver ; TISSUE ; ACCUMULATION ; COMPLEX ; LIGAND ; COMPLEXES ; REPERFUSION ; RAT ; blood flow ; KINETICS ; ISCHEMIA ; myocardium ; BAT ligands ; BMS-181321 ; HYPOXIC TISSUE MARKER ; ischaemia ; nitroimidazole ; RAT-HEART ; TC-99M-MIBI ; technetium ; TECHNETIUM-99M-NITROIMIDAZOLE BMS181321
    Abstract: Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or Tc-99m have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (TcO)-Tc-99m(BAT-NI), a new Tc-99m complex comprising the nitroimidazole ligand, 2,10- dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)- butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(TcO)-Tc-99m(BAT-I)], (b) the 2- nitroimidazole functionality was replaced by a Br atom [(TcO)- Tc-99m(BAT-Br)] and (c) the (TcO)-Tc-99m(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((IP)-I-125- NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (TcO)-Tc-99m(BAT-NI), 99mTcO(BAT- I) and (TcO)-Tc-99m(BAT-Br), respectively. In contrast, (IP)-I- 125-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (TcO)-Tc-99m(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (TcO)-Tc-99m(BAT-NI) in ischaemic tissue and an IN of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (TcO)-Tc- 99m(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (TcO)-Tc-99m(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (TcO)-Tc-99m(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo
    Type of Publication: Journal article published
    PubMed ID: 12574972
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  • 36
    Keywords: AB-INITIO ; PEPTIDE ; SPECTRA ; IN-VITRO ; IN-VIVO ; IONS ; mechanisms ; SPECTROSCOPY ; IDENTIFICATION ; MOBILITY ; fragmentation ; PEPTIDES ; DISSOCIATION ; cyclic depsipeptide ; destruxin ; DESTRUXINS ; GLYCYLGLYCINE ; MAIN FRAGMENTATION PATHWAYS ; PROTONATED PEPTIDES ; quantum chemical calculations ; relative and total energy ; roseotoxin ; RRKM ; Trichothecium
    Abstract: High-performance liquid chromatography and tandem mass spectrometry (HPLC/MS/MS) was used for the detection of cyclic hexadepsipeptides roseotoxins produced by Trichothecium roseum. Roseotoxins were found in both submerged standard cultivation on Czapek-Dox medium and in vivo cultivation extract obtained from an apple. Roseotoxin chromatographic profiles from these two experiments were compared. Product-ion collision-induced dissociation (CID) spectra obtained on an ion trap (electrospray ionisation, ESI) were used for the identification of natural roseotoxins; A, B, C and of minor destruxins; A and B. The dissociation behavior of roseotoxins is discussed in terms of a fragmentation scheme proposed for describing the dissociation pathways of cyclic peptides. This scheme involves opening of the cyclopeptide ring via formation of oxazolone derivatives and fragmentation of the resulting linear species, which have a free N-terminus and an oxazolone ring at the C- terminus. Some aspects of this fragmentation scheme are underlined by modeling the dissociation channels of roseotoxin A using quantum chemical calculations. The structures of roseotoxin A and destruxin B were verified by nuclear magnetic resonance (NMR) spectroscopy. Structures of three new minor natural roseotoxins [Val(4)]RosA, [MeLxx(4)]RosA and [MeLxx(4)]RosB were deduced by ion cyclotron resonance Fourier transform mass spectrometry (ICR-FT-MS) and ion trap tandem mass spectrometry by examining the pre-separated roseotoxin fraction
    Type of Publication: Journal article published
    PubMed ID: 12748394