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The Immunological System and Neoplasia
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
All cells of multicellular organisms except the germ line cells have a defined life span, and their cell cycle is tightly regulated by interconnected pathways. A balance between cell division and programmed cell death or apoptosis is essential to maintain stability within multicellular organisms. The proportion of cells undergoing division versus apoptosis is high during embryonal development and remains high for certain cells (e.g., hemopoietic stem cells). in most tissues cell division slows down after embryonal development has been completed, but the balance can be changed in favor of increased replication when tissues need to regenerate. Two important mechanisms play a role in controlling the cell cycle. Proto-oncogenes are positive regulators driving cells out of the G0 phase into cell division and thus proliferation. Proto-oncogenes are often switched off after homeostasis has been reached. Negative regulators or tumor suppressor genes inhibit cell division and thus proliferation. Cells unable to complete the cell cycle will enter apoptosis, which is the default pathway. Tumors (from tumere, meaning “to swell”) can develop when cells proliferate in an uncontrolled manner or when cells are prevented from entering the apoptotic pathway, while normal cell division continues. Tumors may regress or progress depending on a complex set of factors.
Chromosome Pairing and Fertility in Plant Hybrids
Published in Christopher B. Gillies, Fertility and Chromosome Pairing: Recent Studies in Plants and Animals, 2020
The fertility of a hybrid may also be reduced by irregularities in meiosis of germ line cells. Conventional light microscopy may reveal that chromosomes pair regularly during meiotic prophase, but fail to form chiasmata due to problems of homology arising from structural or numerical rearrangements of the genome, or to impairment of the mechanism of chiasma formation due to genic imbalance resulting from hybridity. The inevitable consequences are that the chromosomes desynapse and disjoin irregularly at anaphase I. The capacity of nonhomologous or homoeologous chromosomes to form chiasmata can be used to some advantage in gauging the relatedness of the genomes of the hybrid from an evolutionary point of view. In other words, the more regular the chiasmate association of chromosomes at metaphase I, the more closely related the chromosomes are likely to be from a genetic or structural viewpoint. Indeed, it is cytological observations of this nature which have helped cytogeneticists unravel the evolution of natural allopolyploids, such as wheat and tobacco, which contain a combination of distinct but similar genomes.
Genetic disorders, skeletal dysplasias and malformations
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Fergal Monsell, Martin Gargan, Deborah Eastwood, James Turner, Ryan Katchky
Chromosomes can be identified and numbered by microscopic examination of suitably prepared blood cells or tissue samples; the cell karyotype defines its chromosomal complement. Somatic (diploid) cells should have 46 chromosomes: 44 (numbers 1–22), called autosomes, are disposed in 22 homologous pairs – one of each pair being derived from the mother and one from the father, both carrying the same type of genetic information; the remaining 2 chromosomes are the sex chromosomes, females having two X chromosomes (one from each parent) and males having one X chromosome from the mother and one Y chromosome from the father. Germ-line cells (eggs and sperm) have a haploid number of chromosomes (22 plus either an X or a Y). This is the euploidic situation; abnormalities of chromosome number would lead to an aneuploidic state.
Fatherhood during dabrafenib and trametinib therapy for metastatic melanoma
Published in Acta Oncologica, 2018
Emilia Cocorocchio, Laura Pala, Angelo Battaglia, Sara Gandini, Fedro Alessandro Peccatori, Pier Francesco Ferrucci
Dabrafenib and Trametinib are both FDA pregnancy category D drugs. Dabrafenib is known to be teratogenic and embryotoxic in rats when used at doses three times the human exposure at the recommended clinical dose. In particular, studies on rats and dogs using repeated doses of dabrafenib (≥0.2 times as compared with the human clinical exposure based on AUC), showed significant testicular degeneration/depletion which was still present following a four-week recovery period. Therefore, preclinical studies demonstrated that Dabrafenib may impair fertility in males and cause fetal harm by interfering with BRAF physiological function, which is essential for the developing embryo. Speculatively, the BRAF/MEK inhibitors act by inhibiting only the mutated forms of the genes involved on MAPK pathway, while on healthy cells, including spermatogonial cells, they could have paradoxical effects. In fact, although there are no known effects induced by simultaneous BRAF/MEK inhibition on spermatogenesis nor demonstrated consequences at the level of spermatogonia, we cannot exclude an induced mutagenesis on germ line cells similar to that observed with chemotherapies. There is only one case report of a 37-year-old woman with metastatic melanoma who got pregnant during treatment with the BRAF inhibitor Vemurafenib. Despite a pronounced antitumoral treatment effect, the fetal growth curve was impacted with a constantly reduced growth parameters during gestation. The patient stopped vemurafenib during the last three months of pregnancy and delivered a 1028 g healthy newborn infant at 30 weeks of gestation [9].
A technical assessment of the porcine ejaculated spermatozoa for a sperm-specific RNA-seq analysis
Published in Systems Biology in Reproductive Medicine, 2018
Marta Gòdia, Fabiana Quoos Mayer, Julieta Nafissi, Anna Castelló, Joan Enric Rodríguez-Gil, Armand Sánchez, Alex Clop
One of the main challenges for the study of the spermatozoa transcriptome is the extremely low RNA yield and high fragmentation of the transcripts typically present in these cells, as the standard RNA-seq chemistry normally requires a large amount (1 µg) of good-quality RNA. To overcome this challenge, new protocols to prepare high quality RNA-seq libraries from samples containing only tiny amounts (200 pg) of highly degraded RNA (e.g., paraffin-embedded tissues) have been developed and already tested and compared in human sperm (Mao et al. 2014). A human mature sperm cell is estimated to contain a 600-fold lower amount of RNA than a somatic cell (Zhao et al. 2006). As a typical ejaculate contains somatic cells – mainly leukocytes, keratinocytes and other type of epithelial cells – as well as germ line cells from different stages of spermatogenesis (Patil et al. 2013), the study of the spermatozoa transcriptome requires removing these RNA-rich cells for an unbiased analysis.
Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells
Published in International Journal of Radiation Biology, 2019
Savneet Kaur Bains, Kim Chapman, Scott Bright, Anish Senan, Munira Kadhim, Predrag Slijepcevic
The DDR pathway can be activated not only due to DNA damage response but also due to telomere shortening. Telomeres are TTAGGG tandem repeat sequences (Moyzis et al. 1988; Blackburn 1991) found at the end of each chromosome (Muller 1938), acting as caps that protect chromosome ends from fusing with each other (Griffiths et al. 1999; de Lange 2005). In recent years, telomere maintenance has been linked with the DNA damage response process (d’Adda di Fagagna et al. 2004; Slijepcevic 2006, 2007; Lydall 2009). Telomeres serve to prevent recognition of natural DNA ends as pathological DNA double-strand breaks (DSBs) by cellular DNA damage response machinery. As normal somatic cells age, telomeres become shorter due to the end replication problem (Watson 1972; Olovnikov 1973), which eventually causes cell senescence. In cancer cells and germ line cells, telomere length is maintained. The most common pathway through which the maintenance takes place is the enzyme telomerase. Telomerase consists of two major subunits; hTERT, a catalytic subunit and TERC, an RNA component (Greider and Blackburn 1989; Feng et al. 1995; Kilian et al. 1997; Espejel et al. 2002). Together with some smaller components, they form a reverse transcriptase-like enzyme which synthesizes telomeric DNA. Another pathway through which telomeres are maintained is the alternative lengthening of telomeres pathway (ALT). The ALT pathway is involved in the maintenance and elongation of telomeres in approximately 10% of human cancers. While normal human somatic cells do not normally display detectable ALT activity some studies are showing that ALT and telomerase can coexist (Cerone et al. 2001).