Introductory Remarks
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Chromosomal amplification/repetition refers to the presence of extra piece from another chromosome that leads to multiple copies of all chromosomal regions and increases the dosage of the genes located within. Chromosomal deletion refers to loss of large chromosomal regions including certain genes (with interstitial deletion being defined as an intra-chromosomal deletion that removes a segment of DNA from a single chromosome and thus apposes previously distant genes, and loss of heterozygosity being loss of one allele, either by a deletion or a genetic recombination event, in an organism with two different alleles). Chromosomal translocation refers to interchange of genetic parts from nonhomologous chromosomes, and chromosomal inversion refers to reversion of the orientation of a chromosomal segment [6].
Genetic disease
Janet M Rennie, Giles S Kendall in A Manual of Neonatal Intensive Care, 2013
Remember that apart from autosomal dominant and recessive inheritance, and X-linked disorders, genetic disease can be transmitted via mitochondrial DNA (exclusively from the female line, although both males and females can be affected) or by genetic imprinting. An imprinted gene has been marked during meiosis, to indicate the parent from whom it comes. For some genes it appears to be important not only to inherit two copies of that gene but also to inherit one from each parent. A good example is the presence of a small deletion of chromosome 15q, which has a different effect depending upon which chromosome 15 is deleted. If the deletion occurs on the chromosome inherited from a child’s normal father, the child will develop Prader–Willi syndrome. If the deletion occurs on the chromosome inherited from a child’s normal mother, the child will develop a completely different clinical condition, Angelman syndrome. Other conditions that show imprinting effects include Russell–Silver syndrome, Beckwith–Wiedemann syndrome, and the rare condition of transient neonatal diabetes mellitus.
Identification and Use of Biomarkers in Preclinical Toxicologic Safety Assessment
Anthony P. DeCaprio in Toxicologic Biomarkers, 2006
However, there are two major issues limiting the interpretive use of GM mice. First, the phenotypic changes seen may more closely mimic developmental defects from complete loss of target and not be representative of the more likely partial inhibition in an adult population administered a drug. In addition, the gene deletion may result in embryonic lethality and assessment of an adult phenotype would not be possible. Additional biomarkers, assays, or investigative studies may be necessary at some point to provide insight into the relevance and mechanism of the potential toxicity in an adult population for a toxicity identified using GM mice. Second, in many cases the embryonic or developmental loss of a target does not affect the development of an animal, which appears phenotypically normal. This is widely acknowledged to be due to some level of functional redundancy or compensatory mechanism allowing for maintenance of normal function (5,7). This outcome may, in fact, predict the outcome in the adult population; alternatively, the compensatory mechanisms may mask a potential effect.
Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation
Published in OncoImmunology, 2021
Wei Nie, Lu Gan, Xin Wang, Kai Gu, Fang-Fei Qian, Min-Juan Hu, Ding Zhang, Shi-Qing Chen, Jun Lu, Shu-Hui Cao, Jing-Wen Li, Yue Wang, Bo Zhang, Shu-Yuan Wang, Chang-Hui Li, Ping Yang, Mi–Die Xu, Xue-Yan Zhang, Hua Zhong, Bao-Hui Han
There were also some limitations to our study. First, the sample size of our study and validation cohorts was moderate, which might limit the power of conclusions. Second, and the results should be considered hypothesis generating rather than hypothesis testing since this was a retrospective study. Third, adverse events in different groups could not be assessed due to insufficient data. Fourth, STK11 and KEAP1 mutations are common in lung adenocarcinoma, but less in squamous NSCLC, especially for STK11. The inclusion of squamous carcinoma may introduce a source of bias. Fifth, STK11 and KEAP1 are located on the end of the short arm of chromosome 19.58,59 Therefore, loss of both genes can occur by deletion of the short arm of this chromosome. Because no copy number variation data was available in this study, we cannot exclude effects of heterozygous loss of one or both genes after chromosome deletion or by loss of heterozygosity. Lastly, we could not get the data about which chemotherapeutic drugs were used in patients before treatment with atezolizumab or docetaxel. Thus, we could not assess whether the absence of response to any chemotherapy could predict the absence (or presence) of response to atezolizumab.
Are PIEZO1 channels a potential therapeutic target for heart failure? Getting to the heart of the matter
Published in Expert Opinion on Therapeutic Targets, 2023
The mouse data outlined above raise the question of whether PIEZO1 antagonism could be a route to new therapies for heart failure, but more research is needed. For various reasons, genetic deletion studies do not necessarily indicate what would happen in therapeutic situations. Small-molecule, biological and depletion approaches of medical therapies usually reduce rather than completely remove the effect of a gene. Such attenuations could be advantageous here, paving the way to blunted PIEZO1 excess while sparing PIEZO1 physiological functions (Figure 1). To test such concepts experimentally, we would need to discover suitable PIEZO1 antagonists and investigate their effects in small and large animal models of different types of heart failure that incorporate risk factors and comorbidities, particularly in treatment protocols and measuring biomarkers that are relevant to clinical settings. We would then need to progress promising antagonists to human trials, guiding their design to the most relevant disease situations. A therapeutic window may need to be established through dosing studies that quantify potential adverse effects.
Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy
Published in Current Eye Research, 2021
Varun Kumar, Mohammad Ali Shariati, Louise Mesentier-Louro, Angela Jinsook Oh, Kristina Russano, Jeffrey L. Goldberg, Yaping Joyce Liao
An important limitation of this study is the use of a genetic deletion model. It is scientifically important to assess the impact of complete elimination of Dusp14 expression, but there may be developmental impact of Dusp14 KO on the visual pathway and protein expression. Future AION studies using AAV-mediated knockdown of Dusp14 and comprehensive characterization of other MAPK family members can help confirm our findings in Dusp14 KO animals. For example, it will be important to characterize the role of other MAPK family members such as JNK and p38 in RGCs and in optic nerve axonal neuroprotection for Dusp14 knockout mice. Also, future work could be directed at characterizing the temporal expression profile of MAPK family members’ expression and activation, which might be neuroprotective or detrimental depending on timing after ischemic insult. Finally, it will be important to extend these anatomic studies to functional assays, for example to investigate preservation of visual acuity in Dusp14 knockout mice after AION.
Related Knowledge Centers
- Chromosomal Crossover
- DNA
- Mutation
- Nucleobase
- Nucleotide
- Synapsis
- Meiosis
- Genetics
- Chromosome
- DNA Base Flipping