453 research outputs found

    Telomere length and telomerase activity in malignant lymphomas at diagnosis and relapse

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    Telomere length maintenance, in the vast majority of cases executed by telomerase, is a prerequisite for long-term proliferation. Most malignant tumours, including lymphomas, are telomerase-positive and this activity is a potential target for future therapeutic interventions since inhibition of telomerase has been shown to result in telomere shortening and cell death in vitro. One prerequisite for the suitability of anti-telomerase drugs in treating cancer is that tumours exhibit shortened telomeres compared to telomerase-positive stem cells. A scenario is envisioned where the tumour burden is reduced using conventional therapy whereafter remaining tumour cells are treated with telomerase inhibitors. In evaluating the realism of such an approach it is essential to know the effects on telomere status by traditional therapeutic regimens. We have studied the telomere lengths in 47 diagnostic lymphomas and a significant telomere shortening was observed compared to benign lymphoid tissues. In addition, telomere length and telomerase activity were studied in consecutive samples from patients with relapsing non-Hodgkin's lymphomas. Shortened, unchanged and elongated telomere lengths were observed in the relapse samples. The telomere length alterations found in the relapsing lymphomas appeared to be independent of telomerase and rather represented clonal selection random at the telomere length level. These data indicate that anti-telomerase therapy would be suitable in only a fraction of malignant lymphomas. © 2000 Cancer Research Campaig

    The variable functional effects of the pacing site in normal and scarred ventricles

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    The pacing site has been shown to influence functional improvement with cardiac resynchronization therapy. We evaluated the effects of the pacing site on left ventricular (LV) function in an animal model. Equilibrium radionuclide angiography was acquired in sinus rhythm (NSR) and with ventricular pacing, from three pacing sites in seven normal and eight infarcted dogs. QRS duration, electrical activation pattern, wall motion, LV ejection fraction (EF), synchrony of ventricular contraction, and mean arterial pressure (MAP), were related to the pacing site and infarct size, during each of 120 episodes. Little changed during pacing in normals. In infarcted dogs, LV wall motion, and synchrony worsened, LVEF and MAP often fell. These changes related to altered activation patterns which were influenced by the pacing site but were not related to infarct size. Hemodynamic and functional LV changes after infarction were found to vary with the pacing site and associated conduction and synchrony

    Cardiogenesis with a focus on vasculogenesis and angiogenesis

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    The initial intraembryonic vasculogenesis occurs in the cardiogenic mesoderm. Here, a cell population of proendocardial cells detaches from the mesoderm that subsequently generates the single endocardial tube by forming vascular plexuses. In the course of embryogenesis, the endocardium retains vasculogenic, angiogenic and haematopoietic potential. The coronary blood vessels that sustain the rapidly expanding myocardium develop in the course of the formation of the cardiac loop by vasculogenesis and angiogenesis from progenitor cells of the proepicardial serosa at the venous pole of the heart as well as from the endocardium and endothelial cells of the sinus venosus. Prospective coronary endothelial cells and progenitor cells of the coronary blood vessel walls (smooth muscle cells, perivascular cells) originate from different cell populations that are in close spatial as well as regulatory connection with each other. Vasculo‐ and angiogenesis of the coronary blood vessels are for a large part regulated by the epicardium and epicardium‐derived cells. Vasculogenic and angiogenic signalling pathways include the vascular endothelial growth factors, the angiopoietins and the fibroblast growth factors and their receptors

    Bone mineral density by digital X-ray radiogrammetry is strongly decreased and associated with joint destruction in long-standing Rheumatoid Arthritis: a cross-sectional study

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    <p>Abstract</p> <p>Background</p> <p>The aims were to explore bone mineral density (BMD) by digital X-ray radiogrammetry (DXR) in postmenopausal women with long-lasting rheumatoid arthritis (RA) in relation to dual x-ray absorptiometry (DXA)-BMD, joint destruction by conventional radiographs and disease related variables in a cross-sectional study.</p> <p>Methods</p> <p>Seventy-five postmenopausal women with RA were examined by DXA measuring DXA-BMD of the forearm, total hip and lumbar spine, by scoring joint destruction on plain radiographs by the method of Larsen and by DXR-BMD in metacarpals two to four. The DXR-BMD results of the RA women were compared with an age and sex-matched reference database. A function of DXR-BMD in relation to age and disease duration was created. Associations were investigated by bivariate and multiple linear regression analyses.</p> <p>Results</p> <p>DXR-BMD was strongly decreased in RA patients compared to the reference database (p < 0.001). Calculations showed that DXR-BMD was not markedly influenced the first years after diagnosis of RA, but between approximately 5-10 years of disease there was a steep decline in DXR-BMD which subsequently levelled off. In multiple regression analyses disease duration, CRP and DXR-BMD were independent variables associated with Larsen score (R<sup>2</sup>= 0.64). Larsen score and BMD forearm were independent determinants of DXR-BMD (R<sup>2 </sup>= 0.79).</p> <p>Conclusions</p> <p>DXR-BMD was strongly reduced and associated with both Larsen score and DXA-BMD forearm in these postmenopausal women with RA implying that DXR-BMD is a technique that reflects both the erosive process and bone loss adjacent to affected joints.</p

    Development of the Pulmonary Vein and the Systemic Venous Sinus: An Interactive 3D Overview

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    Knowledge of the normal formation of the heart is crucial for the understanding of cardiac pathologies and congenital malformations. The understanding of early cardiac development, however, is complicated because it is inseparably associated with other developmental processes such as embryonic folding, formation of the coelomic cavity, and vascular development. Because of this, it is necessary to integrate morphological and experimental analyses. Morphological insights, however, are limited by the difficulty in communication of complex 3D-processes. Most controversies, in consequence, result from differences in interpretation, rather than observation. An example of such a continuing debate is the development of the pulmonary vein and the systemic venous sinus, or “sinus venosus”. To facilitate understanding, we present a 3D study of the developing venous pole in the chicken embryo, showing our results in a novel interactive fashion, which permits the reader to form an independent opinion. We clarify how the pulmonary vein separates from a greater vascular plexus within the splanchnic mesoderm. The systemic venous sinus, in contrast, develops at the junction between the splanchnic and somatic mesoderm. We discuss our model with respect to normal formation of the heart, congenital cardiac malformations, and the phylogeny of the venous tributaries

    Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing

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    PURPOSE: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.EXPERIMENTAL DESIGN: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted re-sequencing and explored potential clinical implications in a multinational cohort of 175 SMZL patients.RESULTS: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%) and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time-to-first-treatment (0.12 vs. 1.11 yrs; P=0.01). In multivariate analysis mutations in NOTCH2 (HR 2.12, 95%CI 1.02-4.4, P=0.044) and 100% germline IGHV gene identity (HR 2.19, 95%CI 1.05-4.55, P=0.036) were independent markers of short time-to-first-treatment, while TP53 mutations were an independent marker of short overall survival (HR 2.36, 95% CI 1.08-5.2, P=0.03).CONCLUSIONS: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.<br/

    Reduced repair of 8-hydroxyguanine in the human breast cancer cell line, HCC1937

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    BACKGROUND: Breast cancer is the second leading cause of cancer deaths in women in the United States. Although the causes of this disease are incompletely understood, oxidative DNA damage is presumed to play a critical role in breast carcinogenesis. A common oxidatively induced DNA lesion is 8-hydroxyguanine (8-OH-Gua), which has been implicated in carcinogenesis. The aim of this study was to investigate the ability of HCC1937 and MCF-7 breast cancer cell lines to repair 8-OH-Gua relative to a nonmalignant human mammary epithelial cell line, AG11134. METHODS: We used oligonucleotide incision assay to analyze the ability of the two breast cancer cell lines to incise 8-OH-Gua relative to the control cell line. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the levels of 8-OH-Gua as its nucleoside, 8-OH-dG in the cell lines after exposure to H(2)O(2 )followed by 30 min repair period. Protein expression levels were determined by Western blot analysis, while the hOGG1 mRNA levels were analyzed by RT-PCR. Complementation of hOGG1 activity in HCC1937 cells was assessed by addition of the purified protein in the incision assay, and in vivo by transfection of pFlagCMV-4-hOGG1. Clonogenic survival assay was used to determine sensitivity after H(2)O(2)-mediated oxidative stress. RESULTS: We show that the HCC1937 breast cancer cells have diminished ability to incise 8-OH-Gua and they accumulate higher levels of 8-OH-dG in the nuclear genome after H(2)O(2 )treatment despite a 30 min repair period when compared to the nonmalignant mammary cells. The defective incision of 8-OH-Gua was consistent with expression of undetectable amounts of hOGG1 in HCC1937 cells. The reduced incision activity was significantly stimulated by addition of purified hOGG1. Furthermore, transfection of pFlagCMV-4-hOGG1 in HCC1937 cells resulted in enhanced incision of 8-OH-Gua. HCC1937 cells are more sensitive to high levels of H(2)O(2 )and have up-regulated SOD1 and SOD2. CONCLUSION: This study provides evidence for inefficient repair of 8-OH-Gua in HCC1937 breast cancer cell line and directly implicates hOGG1 in this defect
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