The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and ß-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45min) in plasma to a maximum concentration of 170±185μg/L (mean±SD). Clearance was high (mean 57.9L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (<1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma ß-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.
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http://dx.doi.org/10.1016/j.ejps.2015.10.001 | DOI Listing |
ACS Omega
January 2025
Department of Physics, Lehigh University, Bethlehem, Pennsylvania 18015, United States.
DNA nucleobases are important in DNA sequencing, disease testing linked to genes, and disease treatment. Here, we report density functional calculations investigating the adsorption of guanine (G), adenine (A), thymine (T), and cytosine (C) on armchair graphene nanoribbons (AGNR) - a gapped semiconductor. Their adsorption energies, charge transfer, work function, and electrical properties were calculated.
View Article and Find Full Text PDFTalanta
January 2025
The Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China. Electronic address:
Electrochemical bioassays that rely on sensor interfaces based on immobilized DNA probes often encounter challenges such as complex fabrication processes and limited binding efficiency. In this study, we developed a novel electrochemical bioassay that bypasses the need for probe immobilization by employing a solution-phase nucleic acid reaction to create interfacial barriers on unmodified electrodes, enabling rapid, just-in-time sensor interface formation. Specifically, a 3'-phosphorylated recognition probe was used to identify the target microRNA-21 (miR-21), followed by target recycling facilitated by duplex-specific nuclease (DSN), which resulted in extensive hydrolysis of the recognition probe into DNA fragments with 3'-hydroxyl ends.
View Article and Find Full Text PDFSignal Transduct Target Ther
January 2025
Centre de Recherche INSERM Center for Translational and Molecular Medicine, 21000, Dijon, France.
In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies.
View Article and Find Full Text PDFJ Phys Chem A
January 2025
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States.
Theoretical simulations of electron detachment processes are vital for understanding chemical redox reactions, semiconductor and electrochemical properties, and high-energy radiation damage. However, accurate calculations of ionized electronic states are very challenging due to their open-shell nature, importance of electron correlation effects, and strong interactions with chemical environment. In this work, we present an efficient approach based on algebraic diagrammatic construction theory with polarizable embedding that allows to accurately simulate ionized electronic states in condensed-phase or biochemical environments (PE-IP-ADC).
View Article and Find Full Text PDFWorld J Microbiol Biotechnol
January 2025
Key Laboratory of Smart Breeding (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Tianjin Agricultural University, Tianjin, 300392, P.R. China.
Revealing the differences of metabolite profiles of H. pluvialis during hyperaccumulation of astaxanthin under the high salinity and nitrogen deficiency conditions was the key issues of the present study. To investigate the optimum NaCl and NaNO concentration and the corresponding metabolic characteristic related to the astaxanthin accumulation in H.
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