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Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
DNA mutation may occur as a result of base substitutions, as well as nucleotide insertions and deletions. Insertions and deletions of nucleotides are very rare in coding DNA. Base substitution is a more common form of mutation in coding DNA, which may have a range of consequences on the function of the gene: a loss of function; a gain in function, often due to stabilisation of the active protein or no net functional effect. An example of a silent substitution yielding no functional effect is seen when an amino acid may be encoded by different codons (e.g. GUA, GAC, GUG and GUU all encode valine), so a substitution of the third base results in no change to the amino acid. At the other extreme is the nonsense mutation, whereby a base substitution results in an early stop codon, which leads to truncation of the polypeptide and a dramatic reduction in function.
Carrier testing
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
DNA mutation analysis has progressively replaced biochemical and haematological tests, though these may still be useful as first-line or screening tests, especially in the haemoglobinopathies. Cystic fibrosis is a good example of a disorder where all phenotypic tests for the carrier state proved unreliable but where testing for mutations now allows determination of which close relatives are carriers. This is made easier by the predominance of one common pathogenic variant in the CFTR gene (delta F508, now more correctly known as c.1521_1523 del CTT; p.Phe508del) in most northern European populations; excluding the carrier state in an unrelated partner may require testing for a much wider range of less frequent variants. The implications of this for population screening in cystic fibrosis are discussed in Chapter 34.
Notes on Genetic and Radiation Control of Senescence
Published in Nate F. Cardarelli, The Thymus in Health and Senescence, 2019
The preceding would indicate that radiation accelerates the aging process. There is ample evidence, however, that this is not the case — in terms of total life-span.337,338 Much depends on the dosage level, but whole body exposure at less than 10 R probably does not shorten life-span.338 DNA levels in mouse thymus did not vary with radiation, but RNA content increased threefold.339 It is also noted that a tumor transplant will cause the mouse host thymus DNA to increase ninefold. Failla claims that since radiation exposure accelerates DNA mutation rate — and then defines aging as an increase in such mutations — that, ergo, radiation causes aging.340 This landmark 1957 paper presented a hypothesis suggesting radiation as the ultimate cause of cancer. Radiation causes DNA mutation, which in turn leads to cancer. The mechanism involves the mutation of the genes that regulates cell proliferation. The hypothesis fails in the light of numerous later studies, but it did set the tone for much early work.
The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer
Published in International Reviews of Immunology, 2022
Marzieh Pirzadeh, Nastaran Khalili, Nima Rezaei
Gastric cancer is the third cause of cancer death worldwide [1]. In addition to genetic factors, many environmental factors are also involved in the etiology of gastric cancer with the most important being H. pylori infection, gastroesophageal reflux disease, obesity and dietary habits [2,3]. H. pylori is a gram negative bacterium which induces a spectrum of diseases spanning from gastritis and peptic ulcer disease to more severe conditions such as mucosa associated lymphoid tissue lymphoma (MALToma) and non-cardia gastric cancer through its various virulence factors [4]. The two most important virulence factors which are related to the intensity of the bacterial infection include vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA). H. pylori, with the help of VacA and CagA, induces a defective autophagy process in gastric epithelial cells, which in turn leads to the aggregation of cytotoxic materials such as reactive oxygen species (ROS) [5]. This increases the risk of cancer development due to DNA mutation, possibly affecting the aryl hydrocarbon receptor (AHR) gene [5,6].
Prospects of topical protection from ultraviolet radiation exposure: a critical review on the juxtaposition of the benefits and risks involved with the use of chemoprotective agents
Published in Journal of Dermatological Treatment, 2018
Nilutpal Sharma Bora, Bhaskar Mazumder, Pronobesh Chattopadhyay
It has been reported that cutaneous malignancies, both melanoma and non-melanoma type get exclusively developed in individuals who get burnt easily or tan rarely. While non-melanomas are readily treatable and preventable, melanomas can prove to be fatal (35). Skin cancer development through solar UVB radiation is a multistage process involving three well defined stages represented by initiation, promotion, and progression; each of which are mediated via changes in various cellular, biochemical, and molecular changes. Irreversible DNA mutation involving genetic alterations make up the tumor initiation process. This is followed by tumor promotion which involves clonal expansion of initiated cells by alterations in signal transduction pathways and considered to be reversible. Finally, tumor progression involves malignant metamorphosis of papillomas to carcinomas. Rapid initiation process of UV-induced damages makes interventive prevention difficult (36).
Tumor mutational burden in non-immunotherapy patients with heavily pretreated metastatic breast cancer: long-term outcomes from a single institution
Published in Journal of Chemotherapy, 2023
Fan Wu, Mulan Chen, Nani Li, Xiufeng Wu, Weiwei Huang, Xinhua Chen, Kan Chen, Lili Wang, Jian Liu
DNA was extracted from fresh metastatic tumor tissue and paired blood samples using the DNeasy Blood and Tissue Kit (QIAGEN). DNA samples were subjected to targeted massively parallel sequencing. DNA-mutation testing is performed in tumor tissue and corresponding blood samples to determine whether they are somatic or germ cell mutations. Peripheral blood samples are extracted using a fully automated nucleic acid extractor. After the extracted gDNA/cfDNA is of acceptable quality (gDNA concentration >10ng/μl, OD260/OD280 = 1.7-1.9, total mass >200ng), an Illumina standard library is created for high-throughput sequencing.