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Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
Other fetal tissues can be used later in the pregnancy: cultured amniotic cells or fetal blood cells, allowing a double investigation of enzymatic activity on erythrocytic cells and immunological status on lymphoid cells.54 This method, if it represents a lesser risk than the trophoblast biopsy, has the disadvantage of being performed later in the pregnancy (Week 17 to 20 of gestation). Other ID associated with an enzymatic defect, such as the orotate phosphoribosyltransferase-orotidylase decarboxylase, can be diagnosed by the same approach, although their prognosis is far better.
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
Related to 5-FU chemotherapy resistance and TS, higher TS expression in MSI-H is both sporadic (86%) and hereditary (100%). Tumors compared to MSI-negative tumors had been demonstrated as a strong predictive factor for nonresponse (resistant) to adjuvant 5-FU chemotherapy (Gatalica, 2014; Gatalica et al., 2015, 2016). In a poorly differentiated gastric cancer cell line MKN45, the important role of decreased activity of orotate phosphoribosyltransferase (OPRT), which is involved in phosphoribosylation of 5-FU leading to tumor growth inhibition, is also suggested (Tsutani et al., 2008). However, a recent in vitro study in the same cell line (MKN45) hypothesized that irrespective of decreased OPRT levels, a decrease in the intracellular FdUMP level could be a probable mechanism involved in the resistance to 5-FU (Mori et al., 2017). Though most retrospective clinical trials have shown that TYMS genotyping may help predict the 5-FU response, insufficiency of TYMS genotyping alone in accurate prediction of outcome response to 5-FU is underlined (Vignoli et al., 2011). To this end, a comprehensive evaluation of each TYMS polymorphism in large-scale prospective randomized control trials is needed to guarantee the efficacy of PGx testing for TYMS in patients prior to 5-FU chemotherapy treatment.
Porphyromonas gingivalis diffusible signaling molecules enhance Fusobacterium nucleatum biofilm formation via gene expression modulation
Published in Journal of Oral Microbiology, 2023
Yukiko Yamaguchi-Kuroda, Yuichiro Kikuchi, Eitoyo Kokubu, Kazuyuki Ishihara
Eighty-seven genes were downregulated (Table 2), including those encoding protein involved in de novo synthesis of purine (phosphoribosyl amine-glucine ligase, purH, class I SAM-dependent methyltransferase, phosphoribosyl glycinamide formyl transferase, purM, amidophosphoribosyltransferase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purE, and phosphoribosylformylglycinamidine synthetase), proteins involved in de novo pyrimidine synthesis (bifunctional pyr operon transcriptional regulator/uracil phosphoribosyltransferase PyrR, aspartate carbamoyltransferase, dihydroorotase, glutamine-hydrolyzing carbamoyl-phosphate synthase small subunit, carbamoyl-phosphate synthase large subunit, dihydroorotate dehydrogenase electron transfer subunit, dihydroorotate dehydrogenase, orotidine 5’-phosphate decarboxylase, and orotate phosphoribosyltransferase), bioA involved in biotin metabolism, and TonB-dependent receptor.
Proteomic investigations into resistance in colorectal cancer
Published in Expert Review of Proteomics, 2020
David I. Cantor, Harish R. Cheruku, Jack Westacott, Joo-Shik Shin, Abidali Mohamedali, Seong Boem Ahn
Another source of resistance to fluoropyrimidines is the presence of microsatellite instability (MSI), which involves the insertion or deletion of repetitive genetic sequences (typically 1-5bp in length, repeated 15–30 times) into susceptible regions, resulting in alteration to DNA replication processes [5]. However, as a key example of the challenges posed by CRC resistance, TS is only one of several enzymes involved in 5-FU metabolism. These compounding enzymes include thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and uridine phosphorylase (UP); each with demonstrated relationships between their respective activities and sensitivity to 5-FU. Positive correlations have been observed between TP, OPRT, and UP expression and increased susceptibility to 5-FU therapy [34,35], whilst DPD expression inversely corresponded with sensitivity, likely due to its contribution to 5-FU degradation [36].
Uridine triacetate - an antidote in the treatment of 5-fluorouracil or capecitabine poisoning
Published in Expert Opinion on Orphan Drugs, 2019
Similarly, clinical toxicities associated with pharmacogenetic susceptibility to 5-FU often develop more rapidly than in other patients, including dihydropyrimidine dehydrogenase (DPD) deficiency, which affects 3–5% of patients treated with 5-FU [35,36]. Approximately 85% of a standard dose of 5-FU is initially degraded by the action of DPD, providing corresponding toxic overexposure if DPD activity is depressed; and an overdose in and of itself can overwhelm the capacity of DPD to degrade 5-FU [35,36]. Polymorphisms in the genes encoding TYMS and MTHFR can also be associated with increased 5-FU toxicity [37,38]. Moreover, mutations in orotate phosphoribosyltransferase (ORPT) can increase 5-FU anabolism to form toxic intracellular 5-fluorouridine nucleotides and are associated with an allele (Gly213Ala) that has an incidence of 27% in Japan (16–17% population in the US), with homozygotes (frequency of 2.5% in the US) at high risk for rapid onset of serious toxicities [39]. Life-threatening toxicities during capecitabine therapy can be caused by the same gene variants that exacerbate 5-FU toxicity, as well as by over activity of cytidine deaminase, which mediates conversion of capecitabine to 5-FU.