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  • 1
    Keywords: TUMORS ; mechanisms ; ASSOCIATION ; SUSCEPTIBILITY ; ABERRATIONS ; MUTATIONS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; ANEUPLOIDY ; GENOMIC IMBALANCES ; MAFFUCCI SYNDROME ; OLLIER DISEASE
    Abstract: In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of 〉 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases
    Type of Publication: Journal article published
    PubMed ID: 22561519
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  • 2
    Abstract: To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events 〉2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
    Type of Publication: Journal article published
    PubMed ID: 27291797
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  • 3
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0533
    Keywords: mdx Mouse ; Muscle pathology ; Regeneration ; Duchenne muscular dystrophy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ultrastructurally there are some clear differences in the pathology of muscle in X chromosomelinked muscular dystrophy of the mouse (mdx) and Duchenne muscular dystrophy (DMD). In particular the mouse muscle does not become infiltrated by large aggregations of connective tissue. It has been proposed that the differences are due to secondary biochemical changes consequent on the absence of dystrophin in both conditions. If this is the case, attention should be directed to the earliest ultrastructural changes held in common by both disorders. The most conspicuous of these, preceding myofibril breakdown, is dilation of the sarcoplasmic reticulum. Any physiological link between this and the absence of dystrophin remains to be determined. We suggest that in themdx mouse, the widespread myofibre necrosis occurring at 3–4 weeks is triggered by increased mechanical demands causing the lack of dystrophin to become critical at this time. Subsequent regeneration of the myofibres appears to be almost completely successful. The ultimate failure of regeneration in DMD, in contrast, may be due to an additional factors acting in DMD exacerbating the lack of dystrophin. This additional factor may be associated with the plasma membrane lesions (not seen inmdx). Alternatively there may be factors present in the mouse that compensate for the lack of dystrophin. It is pointed out that to understand better the different processes occurring inmdx and DMD we need to learn more about the factors which control the balance between the growth of muscle and the growth of connective tissue in both normal and pathological human and mouse muscle.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0533
    Keywords: Dystrophin ; Dystrophin-associated proteins ; Skeletal muscle ; Duchenne muscular dystrophy ; Dystroglycan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunofluorescence and immunogold labelling were used to localise the 43-kDa dystrophinassociated glycoprotein (43DAG) of the dystrophin-glycoprotein complex in control and Duchenne muscular dystrophy (DMD) biopsies. In control muscle 43DAG was localised by immunofluorescence to the periphery of the fibre and, by immunogold, was further delimited to the plasma membrane. The labelling was indistinguishable from that previously reported for the dystrophin C terminus [5]. Moreover, the distance separating adjacent 43DAG labelling sites (120 nm mode) closely matched that separating dystrophin C-terminal sites. This is strong evidence supporting Ervasti & Campbell's model in which the DAG complex is bound close to the C terminus of dystrophin and in which the DAG complexes are separated by approximately the length of the dystrophin rod [7, 12]. In DMD, where there is a 80–90% reduction in the glycoprotein complex [16], a faint or locally patchy distribution of 43DAG was seen by immunofluorescence. Measurement of nearest-neighbour distances after immunogold labelling showed that in DMD the 43DAG was more dispersed, which is further evidence that dystrophin is normally involved in anchoring the DAGs in the plasma membrane. This is significant because the potential success of dystrophin gene therapy could depend not only on restoring dystrophin but also on restoring the lost DAGs.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0533
    Keywords: Dystrophin ; Muscle degeneration ; Muscle regeneration ; Snake venom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunocytochemistry and Western blotting were used to monitor the fate of dystrophin in the soleus muscle of the rat during a cycle of degeneration and regeneration induced by inoculation of the muscle with the venom of Notechis scutatus scutatus (the Australian tiger snake). In control muscle dystrophin was localised close to the plasma membrane. Dystrophin began to break down 3–6 h after venom inoculation, giving a characteristic discontinuous labelling pattern. At 12 h dystrophin was absent from the plasma membrane, and by 1 day the architecture of the muscle fibres had completely broken down. By 2 days post inoculation regeneration had commenced. The regenerating myofibres possessed well-organised myofibrils and the plasma membrane was intact. Dystrophin was detected by Western blot at 3 days, but was not seen in sections until regeneration of the muscle was well advanced, at 4 days post inoculation. The results suggested that although dystrophin was present in the myofibres at 3 days, it was not incorporated into the plasma membrane until 4 days post inoculation. This may be due to the influence of the functional reinnervation of the regenerating fibres, which occurs at 4–5 days, or to the growing fibres reaching a critical diameter.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0533
    Keywords: Skeletal muscle ; Muscular dystrophy ; Titin ; Desmin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have used monoclonal antibodies to desmin and titin, and a combination of immunofluoescence and immunogold labelling to study the disposition of these two proteins in normal human muscle fibres and in fibres at various stages of degeneration in dystrophic muscle. The normal pattern of desmin labelling, in particular the subsarcolemmal labelling, became disrupted at an early stage of fibre breakdown. There was a change from a transverse to a longitudinal orientation of the labelled intermediate filaments as the myofibrils sheared relative to one another. Thus, while it is probable that the desmin filaments are able to play a role in the mechanical integration of the myofibrils in healthy muscle, our results suggest that they cannot withstand the excessive forces generated by the hypercontraction and stretching of dystrophic muscle. However, small accumulations of desmin persisted between the damaged myofibrils until necrosis reached an advanced stage. In general, the degradation of titin appeared to occur before the degradation of desmin, and at the ultrastructural level, labelling with antibodies to epitopes from parts of the titin molecule close to the A-I-band junction was lost before labelling with an antibody to an epitope in the A-band. This suggests that different regions of the titin molecule break down at different stages in the breakdown of the fibre. We propose that lysis of titin in the I-band may underlie ‘slippage’, an abnormality often seen in dystrophic muscle, in which the A-band slips to one pole of the sarcomere such that it abuts onto the Z-line. Breakdown of the A-band section of titin may facilitate the disassembly of the A-filaments.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 54 (1981), S. 329-330 
    ISSN: 1432-0533
    Keywords: Muscular dystrophy, Duchenne type ; Ultrastructure ; Satellite cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A new organelle found in a case of Duchenne muscular dystrophy is described. It was located at the periphery of a regenerated myofibre close to a satellite cell. It was roughly sperical in shape and 0.30–0.35 μm in diameter. Its internal structure was examined in serial and tilted sections, and consisted of parallel arrays of laminae or, possibly, filaments. The nature of the organelle is briefly discussed.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0533
    Keywords: Muscle ; Regeneration ; Denervation ; Ultrastructure ; Snake toxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study examines the level to which muscle regeneration proceeds in the absence of innervation. Regeneration was monitored in rat soleus muscles following localised injection of a snake toxin, notexin. Muscles which had been concomittantly denervated were compared with those that were normally innervated. Until 3–4 days following toxin administration regeneration is identical in both groups. The muscles contain new myotubes in place of the degenerated “parent” fibres. Thereafter, the non-denervated muscles grow rapidly and by 28 days their myofibres attain the size of those from the contralateral controls. Growth of denervated regenerating muscles, however, is retarded and is superseded by a gradual atrophy. In such muscles we further identify ultrastructural abnormalities from 7 days post-injection. These a re loss of individual myosin filaments and the presence of immature and abnormal configurations of the transverse system and triads. We, thus, conclude that innervation is an obligatory requirement for the restoration of normal myofibrillar and sarcotubular morphology, as well as growth, but is not necessary for the neo-formation of myofibres.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0533
    Keywords: Desmin ; Titin ; Muscle degeneration ; Muscle regeneration ; Snake venom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied the fate of desmin and titin in rat skeletal muscle during a cycle of degeneration and regeneration induced in vivo by the inoculation of a snake venom. Cryosections of muscle were labelled using antibodies to the two proteins, and examined at fixed time points after venom injection. Early pathological changes in the muscle, such as hypercontraction, preceded the loss of desmin. Immunolabelling using anti-desmin antibodies showed that desmin bridges were still intact when adjacent myofibrils were no longer aligned. The results suggested that although the hydrolysis of desmin is not necessary for the hypercontraction of muscle fibres, it probably contributes to complete fibre breakdown. Titin, or at least the part which lies close to the M-line, remained intact longer than desmin, but was also hydrolysed prior to complete disintegration of the fibres. Both desmin and titin were re-expressed in the regenerating myotubes by 2 days after venom inoculation, and became well organised even before the myofibrils became aligned. We conclude that desmin and titin are involved in both establishing and maintaining the structural integrity of the muscle fibres.
    Type of Medium: Electronic Resource
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