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  • 1
    Keywords: ASSOCIATION, CANCER, CANCERS, CANDIDATE, CANDIDATE GENES, case control studies, case-control studies
    Abstract: Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. In addition to the pure genetic studies, gene-environment studies, which simultaneously consider environmental factors, have been increasingly conducted. All SNP studies aim at the identification of the role of inherited cancer susceptibility genes. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data on the heritability of cancer and the importance of environmental factors in cancer etiology, we discuss the likelihood of successful gene-environment studies. The available evidence is not conclusive, but it consistently points to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. We use simulation techniques to examine which situations would favor the application of a gene-environment approach instead of the traditional environmental approach in case-control studies. The results show that well-chosen candidate gene with a relatively low allele frequency may improve the power to detect environmental determinants of a disease. However, this advantage is lost when the number of underlying genes increases. We are concerned about an indiscriminate use of genetic tools for cancers, which are mainly environmental in origin. The likelihood of success for SNP-based gene-environment studies increases if established environmental risk factors are tested on proven candidate genes. Enhancing the likelihood that the disease causation is genetic, for example, by selecting familial cases, may increase the power of the studies, and the rareness of those cases calls for collaborative networks
    Type of Publication: Journal article published
    PubMed ID: 17119199
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; proliferation ; CELL ; COMBINATION ; INHIBITION ; PATHWAY ; PATHWAYS ; TOXICITY ; transcription ; cell line ; LINES ; MICE ; TRANSDUCTION ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; TRANSCRIPTION FACTOR ; REDUCTION ; CELL-LINES ; signal transduction ; SIGNAL ; ANTITUMOR-ACTIVITY ; BONE-MARROW ; culture ; LYMPHOMA ; GLUTATHIONE ; CHROMOSOMAL-ABERRATIONS ; EFFICACY ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; ABERRATIONS ; NF-kappa B ; CISPLATIN ; curcumin ; FACTOR-I ; cell lines ; CANCER-THERAPY ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; ARREST ; multiple myeloma ; INCREASE ; LEVEL ; ASSAYS ; CANCERS ; ENGLAND ; aberration ; antineoplasic effect ; antitumor activity ; bendamustine ; chemoprotection ; clastogenic effect ; GSH level ; myeloma ; ACAD
    Abstract: Curcumin is the pigment of turmeric and has been reported as a signal transduction modulator and inhibitor of transcription factors, for example, NF-kappa B. In our article we found a concentration-dependent cytotoxic activity of curcumin in a panel of eight leukemic cell lines (SKW-3, CEM, U-937, HL-60, HL-60/Dox, K-562, LAMA-84, and AR-230). Additive to synergistic interactions was recorded for combinations with bendamustine and idarubicine in SKW-3 and LAMA-84 cells. Noteworthy, in multiple myeloma cells (RPMI-8226 and U-266) a potentiation of the efficacy of bendamustine by curcumin application was found. Moreover, curcumin increased the bendamustine cytotoxicity in cultures of cells isolated from the bone marrow of a patient with non-Hodgkin's lymphoma (NHL). The increased bendamustine efficacy could be explained by NF-kappa B inhibition, because this factor is activated in many cancers, especially leukemia and multiple myeloma. Curcumin is characterized by low toxicity and was described to have a chemoprotective activity. Therefore, the level of reduced glutathione (GSH) was measured and a concentration-dependent increase of GSH levels was recorded in AR-230 and SKW-3 cells (concentration range 5-25 mu M). Experiments with mice showed significant protection against cisplatin-induced chromosomal aberrations (clastogenic effect) and inhibition of mitoses in bone marrow cells. Curcumin alone caused reduction of the mitotic index. In combination with cisplatin, however, this parameter was increased when compared to cisplatin alone. Our data indicate that curcumin has pleiotropic effects on signal transduction by inhibiting transcription thus exerting antitumor activity. In addition, curcumin has protective and anticlastogenic activity by enhancing the scavenging of free radicals
    Type of Publication: Journal article published
    PubMed ID: 17404048
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  • 3
    Keywords: EXPRESSION ; BLOOD ; INHIBITION ; THERAPY ; HEPATOCELLULAR-CARCINOMA ; liver ; GENOME ; RNA ; transcription ; PATIENT ; DNA ; SERA ; MARKER ; LIVER-TRANSPLANTATION ; CONTRAST ; ACID ; NUCLEIC-ACID ; NUCLEIC-ACIDS ; TARGET ; MUTANT ; STAGE ; early detection ; ASSAY ; resistance ; MARKERS ; PCR ; REGION ; REPLICATION ; DNA-SYNTHESIS ; TARGETS ; SEGMENTS ; SERUM ; THERAPIES ; monitoring ; VIRAL REPLICATION ; differential polyadenylation ; mRNA ; LEVEL ; ASSAYS ; MUTANTS ; PEOPLE ; VIRAL-DNA ; ENGLAND ; SHORT-TERM ; viral ; ACAD ; quantitative ; FULL-LENGTH ; EMERGENCE ; synthesis ; POLYMERASE ; China ; HEPATITIS-B-VIRUS ; circulating HBV DNA ; circulating HBV RNA ; HBV RNA ; lamivudine resistance phenotypes ; SURFACE-ANTIGEN
    Abstract: HBV genome replication intermediates blocked at early stages of minus strand synthesis have been identified in a study on circulating DNA and RNA during short-term lamivudine therapy. This suggested that the inhibition of HBV replication processes in the liver are mirrored in the blood. Levels of circulating HBV mRNA remained largely unaffected. Here we followed therapy with two patients (patients I and 2) up to stages without apparent replication. As in the earlier study, DNA segments produced successively during replication were used as targets for quantitative PCR: X (early minus strand), C (completed minus strand), and preC (nascent plus strand). Corresponding RNA was quantified by RT/PCR. Polyadenylated viral RNA were assayed as full-length T and as truncated (tr) RNAs. Blocked X-region intermediates persisted for about one year. After a period of undetectable HBV DNA viral replication resumed in patient 1 because of the emergence of drug-resistant mutants and in patient 2 because of the discontinuation of therapy. In the former case, X-region intermediates reappeared first, then C- and, finally, preC-region intermediates. Stopping therapy, in contrast, led to a simultaneous reappearance of all three types of intermediates. At low replication levels or its absence, trRNA represented the only polyadenylated viral RNA. Apparently, HBV serum nucleic acid markers allow a study of replication and transcription separately. Specifically, it is concluded (1) that PCR assays for monitoring lamivudine therapy must target the X-gene region and (2) that in the absence of HBV replication, trRNA may constitute a serum marker for HBV expression
    Type of Publication: Journal article published
    PubMed ID: 18837958
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  • 4
  • 5
    Keywords: IN-VIVO ; IFN-GAMMA ; DOWN-REGULATION ; BONE-MARROW ; PROGENITOR CELLS ; INTERFERON ; MOBILIZATION ; SELF-RENEWAL ; mesenchymal stromal cells ; E-SELECTIN
    Abstract: The immune response to infection is a rapid and multifaceted process. Infection affects homeostasis within the hematopoietic stem cell (HSC) niche, as lost immune cells must be replaced by HSCs. During the immune response, interferon is produced. Surprisingly, HSCs respond directly to interferon, entering the cell cycle from even the most dormant state. The complex response of both the HSCs and the niche to infection is a unique platform on which to consider HSC-niche interactions. Here, we comment on the contribution of the immune system to the niche and on the direct and indirect effect that infection has on HSCs in the niche.
    Type of Publication: Journal article published
    PubMed ID: 24611873
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  • 6
    Keywords: ENDOTHELIAL GROWTH-FACTOR ; ACUTE LUNG INJURY ; CARDIOVASCULAR-DISEASE ; RHEUMATOID-ARTHRITIS ; SERUM-LEVELS ; TIE-2 LIGAND ANGIOPOIETIN-2 ; TIE2-EXPRESSING MONOCYTES ; PLASMA LEAKAGE ; BOWEL-DISEASE ; VASCULAR LEAKAGE
    Abstract: Angiogenesis and inflammation are two highly linked processes. In the last decade, several factors with dual function in both of these major pathways have been identified. This review focuses on angiopoietin-2 (Ang-2), an important proangiogenic factor that has more recently been implicated in mediating inflammatory processes as well. Ang-2 is upregulated in multiple inflammatory diseases and has been implicated in the direct control of inflammation-related signaling pathways. As a consequence of its multiple roles, designs for therapeutic targeting of Ang-2 should consider the dual function of this factor in regulating angiogenesis and inflammation.
    Type of Publication: Journal article published
    PubMed ID: 25773744
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  • 7
    Keywords: ACTIVATION, AGE, AGE receptors, ANIMAL-MODEL, ANIMAL-MODELS, BINDING, DEFICIENCY, diabetes, DIABETES
    Abstract: Advanced glycation end products (AGEs), S100/calgranulins, and HMGB1 proteins supposedly play a pivotal role in diabetes mellitus and other chronic inflammatory diseases by promoting cellular dysfunction via binding to cellular surface receptors. Particularly, engagement of the receptor for AGEs (RAGE) has gained major attention because it converts short-lasting cellular activation in sustained cellular dysfunction. Consistently, blockade of ligand-RAGE interaction with soluble RAGE (sRAGE) suppresses chronic cellular activation and dysfunction in animal models of chronic diseases. RAGE(-/-) mice, however, demonstrate that the protection conferred by RAGE deficiency is lower than that mediated by sRAGE. Furthermore, RAGE(-/-) mice can be protected by sRAGE in certain settings of the adaptive immune response. This finding implies that abounding RAGE ligands overworking the RAGE pathway might also activate other receptors
    Type of Publication: Journal article published
    PubMed ID: 16037292
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  • 8
    Keywords: ANOMALOUS DIFFUSION, ARCHIPELAGO, ARTIFACTS, CELL, CELLS, COMPLEX, correlation, CORRELATION SPECTROS
    Abstract: To a large extent the cellular interior is occupied by two complex fluids, the cytoplasm and the nucleoplasm, both of which show a considerable degree of macromolecular crowding. While it is easy to imagine that the chromosomal DNA provides the nucleoplasm with properties similar to a polymer melt, the material properties of the cytoplasm are also affected by the high amount of dissolved macromolecules, the cytoskeletal network, and dispersed organelles. By virtue of the strongly obstructed random motion, reactions in the cytoplasm and nucleoplasm are not comparable to the aqueous conditions commonly used in biochemical experiments. To overcome this gap, a thorough understanding of the material properties of intracellular fluids, and hence transport properties within the cell, is mandatory. Here, we review some recent results on bulk diffusion in living cells and some generic consequences that arise from these observations
    Type of Publication: Journal article published
    PubMed ID: 18096846
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  • 9
    Keywords: 3, ACTIVATION, ALKYLPHOSPHOCHOLINES, ANTILEUKEMIC EFFICACY, APOPTOSIS, ASSAY, CASPASE ACTIVATION, CA
    Abstract: Multiple myeloma (MM) is a frequent hematological malignancy that is incurable despite recent developments, such as proteasome and angiogenic inhibitors. Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is an i.v. injectable alkylphosphocholine with antineoplastic activity based on an unusual mode of action and is currently undergoing clinical trials in leukemia patients. The aim of this investigation was to evaluate the efficacy of erufosine in MM cells and to study the modulation of cell-death pathways. The cytotoxicity of erufosine against three MM cell lines (RPMI-8226, U-266, and OPM-2) was determined by the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide-dye reduction assay. All MM cell lines responded to erufosine, RPMI-8226 cells being most and U-266 being least sensitive. The respective IC50 values were 3.2 and 16.2 mu mol/L. Various cell-death characteristics were studied in response to erufosine, such as morphological changes, oligonucleosomal DNA fragmentation, caspase activation, and poly (ADP)-ribose polymerase cleavage. Erufosine was found to cause cell shrinkage, chromatin condensation, and caspase-8 and -3 activation. Taken together, our data indicate that erufosine is a potential antimyeloma drug eliciting specific features of apoptotic cell death in vitro
    Type of Publication: Journal article published
    PubMed ID: 19723075
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  • 10
    Keywords: IN-VIVO ; PROTEIN ; transcription ; DNA ; DYNAMICS ; ASSOCIATION ; MAMMALIAN-CELLS ; LIVING CELLS ; HETEROCHROMATIN ; H4-K16 ACETYLATION
    Abstract: The eukaryotic nucleus harbors the DNA genome, which associates with histones and other chromosomal proteins into a complex referred to as chromatin. It provides an additional layer of so-called epigenetic information via histone modifications and DNA methylation on top of the DNA sequence that determines the cell's active gene expression program. The nucleus is devoid of internal organelles separated by membranes. Thus, free diffusive transport of proteins and RNA can occur throughout the space accessible for a given macromolecule. At the same time, chromatin is partitioned into different specialized structures such as nucleoli, chromosome territories, and heterochromatin domains that serve distinct functions. Here, we address the question of how the activity of chromatin-modifying enzymes is confined to chromatin subcompartments. We discuss mechanisms for establishing activity gradients of diffusive chromatin-modifying enzymes that could give rise to distinct chromatin domains within the cell nucleus. Interestingly, such gradients might directly result from immobilization of the enzymes on the flexible chromatin chain. Thus, locus-specific tethering of these enzymes to chromatin could have the potential to establish, maintain, or modulate epigenetic patterns of characteristic domain size.
    Type of Publication: Journal article published
    PubMed ID: 24033539
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