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Nanomedicines for the Treatment of Respiratory Diseases
Published in Sarwar Beg, Mahfoozur Rahman, Md. Abul Barkat, Farhan J. Ahmad, Nanomedicine for the Treatment of Disease, 2019
Brahmeshwar Mishra, Sundeep Chaurasia
Lung cancer is the most common cancer worldwide (Parkin et al., 2002) and the second most common cancer in the LSS cohort of the atomic bomb survivors in Hiroshima and Nagasaki. Evidence suggests that environmental exposures such as cigarette smoking and radiation have increased the risks of lung cancer (Cruz et al., 2011). Statistical analysis suggests that more than 90% of lung cancer is caused by these extrinsic factors (Preston et al., 2007). In addition, lung cancer incidence among atomic bomb survivors is strongly associated with radiation, with an estimated excess relative risk per Gy of 0.81 and excess 20 absolute risks per Gy of 7.5 per 10,000 people per year (Preston et al., 2007). Therefore, approaches are imperatively needed to explore how radiation affects the development of lung cancer. A pilot study suggests that mutation frequencies of certain genes (e.g., the TP53 tumor suppressor gene) and methylation levels (e.g., the retrotransposon LINE1) may be associated with radiation exposure. It is widely accepted that the formation of nearly all sorts of tumors is largely owing to the dynamic changes in the genome. There are three types of genes that are responsible for tumorigenesis, which are oncogenes, tumor-suppressor genes and stability genes (Vogelstein and Kinzler, 2004). In the early 1950s, a multistage model was introduced as an essential tool to understand tumorigenesis (Armitage and Doll, 1954). This model describes the tumorigenesis as a process of an infinite number of mutations turning a normal cell into malignant or cancerous cells. It shows that the logarithm of incidence was a linear function of the logarithm of age. With the advances of molecular biology, clonal expansion was recognized as an essential stage in carcinogenesis.
Glossary of scientific and technical terms in bioengineering and biological engineering
Published in Megh R. Goyal, Scientific and Technical Terms in Bioengineering and Biological Engineering, 2018
Transposable element (TE, transposon or retrotransposon) is a DNA sequence that can change its position within the genome, sometimes creating or reversing mutations and altering the cell’s genome size. Transposition often results in duplication of the TE. Barbara McClintock’s discovery of these jumping genes earned her a Nobel prize in 1983.
Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Cancer cells frequently generate an excessive supply of SAM to promote aberrant DNA hypermethylation, a hallmark of carcinogenesis. Multiple mechanisms may underlie the overproduction of SAM in cancer. Glycine N-methyltransferase (Gnmt) knockout in mice causes the hepatic overproduction of SAM (Mudd et al., 2001) and aberrant promoter hypermethylation (Martinez-Chantar et al., 2008), leading to increased incidence of hepatocellular carcinoma. Cancer cells have also been shown to produce excess SAM by bolstering one-carbon cycle, by increasing uptake of methionine via amino acid transporters LAT1 and LAT4 (Fuchs and Bode, 2005; Haase et al., 2007), or overexpression of 3-phosphoglycerate dehydrogenase (PGDH), which boosts the metabolite flux through serine-glycine biosynthesis pathway (Possemato et al., 2011; Locasale et al., 2011). Methionine is the methyl donor for SAM; whereas serum participates in folate cycle, which in turn recycles homocysteine to form methionine. Apart from that, serine contributes to SAM biosynthesis from methionine by promoting de novo ATP biosynthesis. Serine starvation in cancer cells severely depleted ATP levels, SAM/SAH ratio and reduced DNA/RNA methylation (Maddocks et al., 2016). In a recent study, Kottakis et al. elucidated the underlying role of mutational events on promoting the one carbon cycle, SAM production and DNA hypermethylation in pancreatic cancer (Kottakis et al., 2016). It was discovered that inactivation of LKB1 tumor suppressor is synergistic with KRASG12D in promoting pancreatic cancer. LKB1 functions as a metabolic checkpoint that integrates signals on nutrient availability, metabolism and growth. The loss of LKB1 plus KRASG12D was found to induce the expression of multiple serine pathway enzymes (PSAT1, PSPH, SHMT1 and SHMT2), which fuels serine-mediated methionine salvage pathway to sustain SAM production and DNA hypermethylation. Either the silencing of PSAT1 or inhibition of SAM biosynthesis abrogated the tumor promoting effect of LKB1 loss, confirming the oncogenic role of the serine-one carbon cycle-SAM-DNA methylation axis. Importantly, DNA hypermethylation was mapped to the retrotransposon repeats in gene bodies, which affect transcription activities of respective genes. These findings highlight the important role of driver gene mutations in mediating metabolism-epigenetics crosstalk to promote carcinogenesis.
Inter-retrotransposon amplified polymorphism markers revealed long terminal repeat retrotransposon insertion polymorphism in flax cultivated on the experimental fields around Chernobyl
Published in Journal of Environmental Science and Health, Part A, 2020
Veronika Lancíková, Jana Žiarovská
Retrotransposon-based markers have been applied to investigate the genetic variability of flax seeds harvested from the radioactive and control experimental fields in the Chernobyl area. Both methods are based on effective use of retrotransposons clustering in the genome, the phenomenon allowing application of IRAP and iPBS in spite of known dispersed nature of retrotransposons.[44] Herein, flax-specific IRAP and universal iPBS markers have been employed to investigate which marker system is more suitable for identification of flax LTR-retrotransposon changes after chronic radiation stress. Retrotransposon-based IRAP markers have been previously developed and their suitability for flax genetic studies has been confirmed.[45] The IRAP method uses for PCR amplification the specific primers binding to the LTR sequences of retrotransposons. Applicability of the method depends on the presence of suitable LTR sequences allowing the amplification of a region between two different LTR sequences in the genome. The basis of iPBS method is the existence of PBS (Primer Binding Sites) adjacent to the region of 5′ LTR. Unlike the LTR sequences which may vary in different organisms, PBS are universal and conserved among different families of LTR retrotransposons.[38,46]