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Importance All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders. Objective To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality. Design, Setting, and Participants This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2’-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography–tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years., IMPORTANCE: All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders.OBJECTIVE: To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years.EXPOSURES: History of psychiatric illness.MAIN OUTCOMES AND MEASURES: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level.RESULTS: A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P &l

Introduction Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML. Areas covered This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias. Expert opinion TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.

Modifications of nucleic acids (DNA and RNA) from oxidative stress is a potential driver of aging per se and of mortality in age-associated medical disorders such as type 2 diabetes (T2D). In a human cohort, we found a strong prediction of all-cause mortality by a marker of systemic oxidation of RNA in patients with T2D (n = 2672) and in nondiabetic control subjects (n = 4079). The finding persisted after the adjustment of established modifiers of oxidative stress (including BMI, smoking, and glycated hemoglobin). In contrast, systemic levels of DNA damage from oxidation, which traditionally has been causally linked to both T2D and aging, failed to predict mortality. Strikingly, these findings were subsequently replicated in an independent general population study (n = 3649). The data demonstrate a specific importance of RNA damage from oxidation in T2D and general aging., Modifications of nucleic acids (DNA and RNA) from oxidative stress is a potential driver of aging per se and of mortality in age-associated medical disorders such as type 2 diabetes (T2D). In a human cohort, we found a strong prediction of all-cause mortality by a marker of systemic oxidation of RNA in patients with T2D (n = 2672) and in nondiabetic control subjects (n = 4079). The finding persisted after the adjustment of established modifiers of oxidative stress (including BMI, smoking, and glycated hemoglobin). In contrast, systemic levels of DNA damage from oxidation, which traditionally has been causally linked to both T2D and aging, failed to predict mortality. Strikingly, these findings were subsequently replicated in an independent general population study (n = 3649). The data demonstrate a specific importance of RNA damage from oxidation in T2D and general aging.

Background: To evaluate the association of urinary oxidized guanine/guanosine (OxGuo) levels with incident type 2 diabetes (T2D) among older adults. Methods: A nested case-control design was applied with 440 cases of incident T2D and 440 controls, randomly sampled from all 65-75 year-old study participants of the ESTHER study, which is a population-based German cohort study with 14 years of follow-up. Analyses of 8-hydroxy-2′-deoxyguanosine (8-oxo-dGuo; DNA oxidation product) and 8-hydroxyguanosine (8-oxo-Guo; RNA oxidation product) were measured by ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS). The sum of the two OxGuo molecule concentrations was calculated and called OxGuo-UPLC-MS/MS. The corresponding OxGuo-ELISA levels were measured by Cayman's DNA/RNA oxidative damage ELISA, which detects a mix of 8-oxo-dGuo, 8-oxo-Guo and one other OxGuo molecule. Logistic regression was applied and models were adjusted for age, sex, BMI, HbA1c, and C-reactive protein levels. Results: 8-oxo-dGuo and 8-oxo-Guo were highly correlated with each other (r = 0.642) and weakly correlated with OxGuo-ELISA (r = 0.22 and r = 0.14, respectively). OxGuo-ELISA levels were statistically significant associated with T2D incidence (odds ratio (OR) and 95% confidence interval [95%CI] for comparison of top and bottom quartile: 1.77 [1.14; 2.76]). In contrast, the ORs did not increase stepwise from quartile 2 to 4 for neither 8-oxo-Guo, 8-oxo-dGuo levels nor OxGuo-UPLC-MS/MS and comparisons of top and bottom quartile were not statistically significant. In a post-hoc analysis comparing bottom quartile 1 with a combined group of quartile 2–4, the association of OxGuo-UPLC-MS/MS with T2D incidence reached statistical significance (OR [95%CI]: 0.66 [0.46; 0.96]) and was very similar with the one obtained for OxGuo-ELISA (OR [95%CI]: 0.66 [0.45; 0.95]). Conclusions: Although only the measurements of the DNA/RNA oxidative damage ELISA kit of Cayman were sta

Biotin (or Vitamin B7) is a vitamin where deficiency can be caused by inadequate intake. Biotin deficiency is rare, as most people get enough biotin from diet, since many foods contain biotin. In addition to biotin from food, intestinal bacteria can synthesize biotin, which can then be absorbed by the body. Supplementation with biotin has been advocated, mainly due to proposed beneficial effects on skin, nail and hair growth. There is no evidence that high biotin intakes are toxic, but a high intake may interfere with diagnostic assays that use biotin-streptavidin technology. These tests are commonly used to measure plasma concentrations of a wide range of hormones. Erroneous results may lead to misdiagnosis of various endocrine disorders. Supplementation with high-dose biotin has been used experimental for the treatment of diseases (e.g. multiple sclerosis) and high doses are used to obtain effect on nail and hair growth. On this background a demand for tests to determine if there is a risk of obtaining false test results when using biotin-streptavidin based tests have appeared. In this paper we present a method based on column switching liquid chromatography tandem mass spectrometry for the quantification of biotin in plasma and serum and explore the effects of biotin on an immunoassay based on biotin strept(avidin) chemistry.

Among markers for oxidative stress urinary excretion 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and 8-oxo-7,8-dihydro-guanosine (8-oxoGuo) have been widely used in controlled and epidemiological studies, and are considered to represent intracellular markers of oxidation of DNA and RNA in the entire organism, respectively. Although being non-invasive, urinary methods have shortcomings. There is no established method for analysis of 8-oxodGuo and 8-oxoGuo in plasma and the few plasma values presented in the literature vary greatly. We here present a liquid chromatography mass spectrometry method with full validation for analysis of 8-oxodGuo and 8-oxoGuo in plasma. Further, we investigated the basis for our previously physiological model and show that a single plasma sample can be used to estimate the 24-h production of 8-oxoGuo, whereas we challenge the use of urinary 8-oxodGuo/creatinine ratio or plasma 8-oxodGuo as measures of oxidative stress.

Oxidative stress is associated with the development and progression of numerous diseases. However, targeting oxidative stress has not been established in the clinical management of any disease. Several methods and markers are available to measure oxidative stress, including direct measurement of free radicals, antioxidants, redox balance, and oxidative modifications of cellular macromolecules. Oxidatively generated nucleic acid modifications have attracted much interest due to the pre-mutagenic oxidative modification of DNA into 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), associated with cancer development. During the last decade, the perception of RNA has changed from that of a ‘silent messenger’ to an ‘active contributor’, and, parallelly oxidatively generated RNA modifications measured as 8-oxo-7,8-dihydro-guanosine (8-oxoGuo), has been demonstrated as a prognostic factor for all-caused and cardiovascular related mortality in patients with type 2 diabetes. Several attempts have been made to modify the amount of oxidative nucleic acid modifications. Thus, this review aims to introduce researchers to the measurement of oxidatively generated nucleic acid modifications as well as critically review previous attempts and provide future directions for targeting oxidatively generated nucleic acid modifications.

Background: The oxidized guanine nucleosides, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), derived from DNA and RNA, respectively, were used to investigate the importance of oxidative stress to nucleic acids in vivo. High urinary excretion of 8-oxodG is associated with cancer development, whereas high urinary excretion of 8-oxoGuo is associated with mortality in type 2 diabetes. Like creatinine, these small water-soluble molecules are not reabsorbed in the kidney. Therefore, 8-oxo nucleoside/creatinine reciprocal concentration ratios are identical in plasma and urine. The total amount of 8-oxo guanine nucleosides excreted by the kidneys is the product of plasma concentration and glomerular filtration rate. Methods: With relevant equations and an estimated glomerular filtration rate, the 24-h urinary excretion of 8-oxodG and 8-oxoGuo was calculated in 2679 subjects with type 2 diabetes, displaying good correlation with the measured urinary 8-oxo nucleoside/creatinine ratio: DNA oxidation r = 0.86 and RNA oxidation r = 0.84 (p < 0.05 for both). Results: Survival analyses based on the quartiles of the 8-oxodG/creatinine ratio and the quartiles of calculated 24-h urinary excretion rate of the 2679 subjects gave similar hazard ratio estimates for death due to all causes. This finding was similar for the 8-oxoGuo hazard ratio estimates. Conclusions: This study shows that oxidatively generated modifications to DNA and RNA in vivo can be measured using 1) a spot urine sample, normalized to urinary creatinine, 2) 24-h urine, or 3) a single plasma sample based on concentrations of 8-oxo nucleoside and creatinine and glomerular filtration rate.

Major depressive disorder (MDD) affects 350 million people worldwide and is a serious socio-economic burden. The most efficient treatment of MDD is electroconvulsive therapy (ECT), which has been shown to influence the oxidative status believed to be part of the pathophysiology of MDD. We investigated the effects of chronic electroconvulsive stimulation (ECS) on mitochondrial respiration and mitochondrial hydrogen peroxide production, RNA oxidation, and the content of mitochondria in the piriform cortex of the rat. We found reductions of mitochondrial respiration in respiratory states 2 and 3 by 33% and 32%, respectively, and a 23% reduction in electron transfer capacity. RNA oxidation, as measured by 8-oxo-7,8-dihydroguanosine, was increased by 58%, while mitochondrial production of H2O2 was unaffected. The increased oxidative stress may thus be ascribed to extra-mitochondrial sources., Major depressive disorder (MDD) affects 350 million people worldwide and is a serious socio-economic burden. The most efficient treatment of MDD is electroconvulsive therapy (ECT), which has been shown to influence the oxidative status believed to be part of the pathophysiology of MDD. We investigated the effects of chronic electroconvulsive stimulation (ECS) on mitochondrial respiration and mitochondrial hydrogen peroxide production, RNA oxidation, and the content of mitochondria in the piriform cortex of the rat. We found reductions of mitochondrial respiration in respiratory states 2 and 3 by 33% and 32%, respectively, and a 23% reduction in electron transfer capacity. RNA oxidation, as measured by 8-oxo-7,8-dihydroguanosine, was increased by 58%, while mitochondrial production of H2O2 was unaffected. The increased oxidative stress may thus be ascribed to extra-mitochondrial sources.

Isoguanine (2-hydroxyadenine), considered to be a non-natural nucleobase has, however, been shown to occur in the croton bean, butterfly wings and a mollusk. For the first time, to the best of our knowledge, we report the identification of isoguanosine (2-hydroxyadenosine), the ribonucleoside, in humans and mouse. Isoguanosine is identified and quantified in RNA from mouse liver samples and in human urine and cerebrospinal fluid. Isoguanine could not be detected as the 2'-deoxyribonucleoside in mouse liver DNA. It could be speculated that the source of isoguanosine was formation from adenosine during oxidative stress in the body. However, the urinary concentrations of isoguanosine and the levels in the liver found here by using isotope dilution liquid chromatography-tandem mass spectrometry are identical to or exceed those of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro-guanosine. Guanine is the nucleobase that is oxidized the easiest, so it appears spectacular that the levels of isoguanosine are higher than the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro-guanosine. It also appears intriguing that it was only possible to detect the ribonucleoside isoguanosine and not the 2'-deoxyribonucleoside. These observations could indicate that the isoguanosine found is not formed by oxidative stress and could have biological functions.

Objective:Oxidative stress has been suggested to increase after electroconvulsive therapy (ECT); a treatment which continues to be the most effective for severe depression. Oxidative stress could potentially be mechanistically involved in both the therapeutic effects and side-effects of ECT.Methods:We measured sensitive markers of systemic and CNS oxidative stress on DNA and RNA (urinary 8-oxodG/8-oxoGuo, cerebrospinal fluid 8-oxoGuo, and brain oxoguanine glycosylase mRNA expression) in male rats subjected to electroconvulsive stimulations (ECS); an animal model of ECT. Due to previous observations that link hypothalamic-pituitary-adrenal (HPA)-axis activity and age to DNA/RNA damage from oxidation, groups of young and middle-aged male animals were included, and markers of HPA-axis activity were measured.Results:ECS induced weight loss, corticosterone increases (only in middle-aged animals), and decreased cerebral glucocorticoid receptor mRNA expression, while largely leaving the markers of systemic and CNS DNA/RNA damage from oxidation unaltered.Conclusion:These results suggest that ECS is not associated with any lasting effects on oxidative stress on nucleic acids neither in young or middle-aged rats.