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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
During meiosis I, the sister kinetochores are co-oriented such that they are pulled to the same side of the spindle. At the same time, cohesion between sister chromatids along chromosome arms is released, allowing the homologous chromosome to separate. In contrast, cohesion near the centromeres is protected until meiosis II, when it is released to allow sister chromatids to separate (Figure 8.6).
Sex Chromosome Pairing and Fertility in the Heterogametic Sex of Mammals and Birds
Published in Christopher B. Gillies, Fertility and Chromosome Pairing: Recent Studies in Plants and Animals, 2020
Immunocytochemical labeling of kinetochores in human SC spreads has confirmed that synapsis extends beyond the Y kinetochore.194 As mentioned in Section V, recombination nodules are mostly distributed on the distal half of the short arm of the Y axis (Figure 5).
Preimplantation Genetic Testing for Aneuploidies: Where We Are and Where We're Going
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
Andrea Victor, Cagri Ogur, Alan Thornhill, Darren K. Griffin
Mosaicism was first documented in human embryos with FISH [3,4,52,114]. Since then, a number of different mitotic error mechanisms have been proposed to explain mosaicism: mitotic nondisjunction, anaphase lagging, formation of multinuclei and/or micronuclei, centriole/centrosome dysregulation, and endoreplication [102,115–117]. Mitotic nondisjunction means that sister chromatids of a chromosome are not correctly separated during cell division, resulting in one trisomic and one monosomic daughter cell. Anaphase lagging is an event leading to monosomy in one of the daughter cells at mitosis, because a chromatid does not become incorporated into the nucleus. In mosaic embryos, there is a documented increased incidence of monosomies compared to trisomies, suggesting that anaphase lagging might be the principal mechanism creating mosaicism [12,118,119]. Micronuclei, or small nucleus-like structures, are thought to arise when chromosomal material forms its own nuclear membrane. Since proper kinetochores are absent, the chromosomal content of micronuclei are unable to undergo regulated mitosis, likely resulting in mosaicism in daughter cells [116,120]. Finally, endoreplication without subsequent division could hypothetically result in mosaicism but has not been documented for individual chromosomes, but rather for entire chromosomal complements [115].
Favourable outcome of planned pregnancies in systemic sclerosis patients during stable disease
Published in Scandinavian Journal of Rheumatology, 2022
J Braun, A Balbir-Gurman, K Toledano, Y Tavor, Y Braun-Moscovici
Another issue is the impact of ACA positivity on conception and fertility. In our large cohort of SSc patients of fertile age, we identified eight ACA-positive patients. Four patients had failed repeated IVF attempts. Three other patients conceived spontaneously. Two patients underwent successful IVF with uneventful pregnancy and delivery of healthy babies. One of them had had two previous abortions and the IVF was with a donated oocyte. Two out of three patients with spontaneous abortions were positive for ACAs. Disorders of oocyte maturation and early embryonic development abnormalities have been observed in women with ACA positivity (14). ACA may be the essential marker for defective oocytes or embryos in infertile women with any type of ANA (15). The exact mechanism is unknown. In a study performed in mouse oocytes, microinjected centromere kinetochore antibodies were found to interfere with chromosome movement in meiotic and mitotic oocytes (16).
Biomarkers of skin and lung fibrosis in systemic sclerosis
Published in Expert Review of Clinical Immunology, 2019
Dušanka Martinović Kaliterna, Marin Petrić
ATA, first described in 1979, are the most pathognomonic antibodies in SSc [33]. They are directed against the nuclear enzyme topoisomerase and associated with diffuse skin involvement, as well as SSc-related ILD, and are rarely found in other autoimmune diseases [34]. There are multiple lines of evidence of their association with an increased risk of development of different malignancies in SSc [13]. In 2013, Colaci et al. confirmed the association of ATA with lung carcinoma [35]. Considering their correlation with disease activity and skin fibrosis, there are studies showing contradictory results. Some authors deem that ATA levels correlate with disease flares and that seronegative conversion is strongly associated with remission, while others find this data inconclusive [36]. ACA, first described in 1980 by Moroi et al. [37], recognize disk-shaped protein antigens located in the kinetochore chromosome region and they are significantly associated with limited skin changes, peripheral vascular abnormalities and calcinosis [38]. When present in the sera of patients with RP, there is an increased risk for developing lcSSc [39]. Prospective studies with large cohorts proved ACA as predictors of PAH, and negative predictors of ILD [34,40]. ACA titer is rather stable during disease course and does not correlate with disease activity.
Pixantrone: novel mode of action and clinical readouts
Published in Expert Review of Hematology, 2018
Giorgio Minotti, Haiyong Han, Valérie Cattan, Anton Egorov, Francesco Bertoni
In vitro experiments show that pixantrone has little or no effect on cell cycle at therapeutic concentrations (i.e. equal to or lower than plasma Cmax) [25]. Tumor cells exposed to pixantrone undergo mitosis, but with aberrations [25]. Defective kinetochore attachments lead to mis-segregation of chromosomes and generation of micronuclei in pixantrone-treated cells, and cell death occurs only after successive rounds of aberrant mitosis [25]. At the American Association for Cancer Research (AACR) 2017 Annual Meeting, Ng and colleagues presented a study conducted in NHL cell lines further showing that pixantrone (1–100 nM) impairs chromosomal segregation (as indicated by micronuclei formation) without triggering mitotic checkpoint activation [20]. Pixantrone induces less DNA double-strand breaks compared with doxorubicin, as quantified by the number of γH2AX positive foci, although the long-term antitumor effect, measured by long-term clonogenic assays, is similar for the two drugs [20].