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Pest Control in Modern Public Health
Published in Jerome Goddard, Public Health Entomology, 2022
One major concern of entomologists and ecologists is the possible fitness cost to the mosquito, which could lead to transgene silencing, the evolution of “resistance,” or even a restoration of wildtype fitness.37 In the latter, the wildtype mutant would quickly rebound. A rise in drive-resistant alleles in natural populations, especially after mating of transgenic mosquitoes and wildtype mosquitoes, could result in unimagined and undesirable downstream effects.40 Increasing numbers of drive-resistant insects would eliminate the drive through natural selection since the drive itself would likely impart some level of fitness reduction.41 Therefore, we must assess the evolutionary stability of gene drives in nature. Further, effects of releasing a genetically modified insect into the environment are still largely unknown. There could be potential downstream off-target effects such as a potential risk of other mutated pests. Detecting these mutated off-target pests would prove near impossible once GMMs are unleashed in the environment.42 A successful gene drive would require mating between mutants and wildtype mosquitoes, so reliability of the gene to be heritable and effective in these crosses after multiple generations needs to be accurately assessed.41,43
Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
The K27M mutation of the genes for the replacement histone H3.3 is found in 20% of pediatric glioblastoma, and is characteristic of DIPG (see below), but is not found in other pediatric tumors. The prognosis is poor, compared to wild type. It is not seen in adult-type supratentorial GBM, but is reported in adult mid-line tumors.
Individualization of Endocrine Therapy in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amelia B. Zelnak, Ruth M. O’Regan, Clodia Osipo
Several mutant forms of both the ERα and ERβ, another ER isoform, have been identified and previously reviewed (11–13). However, the functional significance of these mutants as a mechanism of antiestrogen resistance is yet to be elucidated. Most of the data demonstrate the existence of splice variants for ERα and ERβ mRNAs without evidence of translation into functional proteins. Most of the tumors express both mutant and wild-type ER with the wild type being the predominant species. A single-point mutation in the ligand-binding domain (LBD) of ERα has been reported (D351Y) that converts tamoxifen and ralox ifene from antiestrogen to estrogens in in vivo and in vitro models of antiestrogen-stimulated MCF-7 tumor cells (14,15). However, the D351Y ERα mutant has yet to be detected in either intrinsic or acquired resistant breast tumors from patients. In addition, mutations in the F-region of the ER have been shown to affect the activities of both E2 and 4-hydroxytamoxifen (40HT), the active metabolite of tamoxifen (16). Therefore, the clinical relevance of ER mutants is unclear to date as a mechanism of resistance to antiestrogens. However, our understanding of ER mutations in response to antiestrogens might lead to the development of better antiestrogens or other drugs for breast cancer treatment.
Astrocytoma and glioblastoma IDH1-wildtype cells colonize tumor vessels and deploy vascular mimicry
Published in Ultrastructural Pathology, 2023
Haitham H. Maraqah, Mones S. Abu-Asab, Han Sung Lee, Orwa Aboud
The astrocytoma IDH1-mutant tumors showed similar abnormal features in the tumor vessels to that of IDH1-wildtype glioblastoma tumors. The tumor cells’ invasion of vessels’ was ubiquitous (Figure 2) and resulted in deformed and abnormal vessel shape and structure (Figure 2a-f). The VWs were thickened with redundant elastic layers of the basement membrane, morphologically distorted, and occupied with lipid and tumor cells (*, Figure 2a-c and e). The vessels’ lumina had lipid inclusions (L) and tumor cell (+). The basal lamina was abnormal and discontinuous as well as partially or totally lacking. Endothelial cells were absent and replaced by the tumor cells; however, this process is occasionally more prominent with more tumor cells forming a circle around on the luminal side, a sign of vascular mimicry (see discussion). The deformed and distorted structure is more prominent in the mutant type than in wildtype.
Gastrointestinal Stromal Tumor Patients with Molecular Testing Exhibit Superior Survival Compared to Patients without Testing: Results from the Life Raft Group (LRG) Registry
Published in Cancer Investigation, 2023
Jerry Call, Jonathan Wojtkowiak, Denisse Evans, Pete Knox, Thomas J. Hughes, Maeven Luedke, Sahibjeet Kaur, Carolyn Tordella, Mary Garland, Paul T. Lim, Norman J. Scherzer, Sara Rothschild, Jonathan Trent
This study investigated whether OS of LRG registry members with mutational testing (Tested) was different compared to members without testing (Untested). Mutations in this manuscript refer to driver mutations as reported by patients (many, but not all include the mutation report) including KIT, PDGFRA, BRAF, NF1, NTRK, SDHA, SDHB, SDHC and SDHC-epimutant. Only driver mutations (listed above) and not secondary mutations (e.g., KIT exons 13,14, 17 and 18) or accessory mutations (e.g., TP53, etc.) are included in this analysis. Patients with Tested and no detectable mutation in KIT or PDGFRA are commonly called KIT/PDGFRA WT. These patients may or may not have further testing. Patients without further testing are still considered as Tested (for the purposes of this analysis) and the gene is listed as “Wildtype”. KIT/PDGFRA WT patients with additional testing (usually Next Generation Sequencing) will have the suspected driver mutation reported (e.g., NF1, SDHx, etc.). The typical mutational testing sequence (flowchart) is described in Supplemental Figure 1. This sequence has varied over time as newer testing becomes available and iSt can vary from patient to patient and from country to country.
In silico high throughput mutagenesis and screening of signal peptides to mitigate N-terminal heterogeneity of recombinant monoclonal antibodies
Published in mAbs, 2022
Xin Yu, Merlinda Conyne, Marc R. Lake, Karl A. Walter, Jing Min
To aid the selection of mutants for future studies, we analyzed titers of all 87 antibodies (including those with the original SPs). The mutants were grouped by the wildtype SPs from which they were derived. The fold change in titer was calculated by dividing the titer of a given antibody produced with a mutant SP, by the titer of the same antibody produced with its original SP. In this way, the difference among the antibodies was normalized. As shown in Supp. Figure 7, some SPs and their mutants appeared to generate lower titers on average (e.g., sp_12, VKII_A18), while some appeared to generate higher titers on average (e.g., sp_14, VH_3-53). Because the number of antibodies produced per SP is relatively small, additional studies are needed to elucidate how SP mutagenesis affects the titer of antibodies.