Past Connectivity but Recent Inbreeding in Cross River Gorillas Determined Using Whole Genomes from Single Hairs.

The critically endangered western gorillas (Gorilla gorilla) are divided into two subspecies: the western lowland (G. g. gorilla) and the Cross River (G. g. diehli) gorilla. Given the difficulty in sampling wild great ape populations and the small estimated size of the Cross River gorilla population, only one whole genome of a Cross River gorilla has been sequenced to date, hindering the study of this subspecies at the population level. In this study, we expand the number of whole genomes available for wild western gorillas, generating 41 new genomes (25 belonging to Cross River gorillas) using single shed hairs collected from gorilla nests. By combining these genomes with publicly available wild gorilla genomes, we confirm that Cross River gorillas form three population clusters. We also found little variation in genome-wide heterozygosity among them. Our analyses reveal long runs of homozygosity (>10 Mb), indicating recent inbreeding in Cross River gorillas. This is similar to that seen in mountain gorillas but with a much more recent bottleneck. We also detect past gene flow between two Cross River sites, Afi Mountain Wildlife Sanctuary and the Mbe Mountains. Furthermore, we observe past allele sharing between Cross River gorillas and the northern western lowland gorilla sites, as well as with the eastern gorilla species. This is the first study using single shed hairs from a wild species for whole genome sequencing to date. Taken together, our results highlight the importance of implementing conservation measures to increase connectivity among Cross River gorilla sites.

Evolving Hybrid Partial Genetic Algorithm Classification Model for Cost-effective Frailty Screening: Investigative Study.

BACKGROUND: A commonly used method for measuring frailty is the accumulation of deficits expressed as a frailty index (FI). FIs can be readily adapted to many databases, as the parameters to use are not prescribed but rather reflect a subset of extracted features (variables). Unfortunately, the structure of many databases does not permit the direct extraction of a suitable subset, requiring additional effort to determine and verify the value of features for each record and thus significantly increasing cost. OBJECTIVE: Our objective is to describe how an artificial intelligence (AI) optimization technique called partial genetic algorithms can be used to refine the subset of features used to calculate an FI and favor features that have the least cost of acquisition. METHODS: This is a secondary analysis of a residential care database compiled from 10 facilities in Queensland, Australia. The database is comprised of routinely collected administrative data and unstructured patient notes for 592 residents aged 75 years and over. The primary study derived an electronic frailty index (eFI) calculated from 36 suitable features. We then structurally modified a genetic algorithm to find an optimal predictor of the calculated eFI (0.21 threshold) from 2 sets of features. Partial genetic algorithms were used to optimize 4 underlying classification models: logistic regression, decision trees, random forest, and support vector machines. RESULTS: Among the underlying models, logistic regression was found to produce the best models in almost all scenarios and feature set sizes. The best models were built using all the low-cost features and as few as 10 high-cost features, and they performed well enough (sensitivity 89%, specificity 87%) to be considered candidates for a low-cost frailty screening test. CONCLUSIONS: In this study, a systematic approach for selecting an optimal set of features with a low cost of acquisition and performance comparable to the eFI for detecting frailty was demonstrated on an aged care database. Partial genetic algorithms have proven useful in offering a trade-off between cost and accuracy to systematically identify frailty.

Using the Mothers Object Relations Scale for early childhood development research in rural India: Findings from the Early Life Stress Sub-study of the SPRING Cluster Randomised Controlled Trial (SPRING-ELS).

Background: The World Health Organization and others promote responsive caregiving to support all children to thrive, particularly in low- and middle-income countries. The 14-item Mother's Object Relations Scales - Short Form (MORS-SF) may be of use in research and public health programmes because of its basis in attachment theory and ability to capture parental feelings towards their child. Methods: We culturally adapted the MORS-SF for use with mothers in the SPRING home visits trial when their infants were 12 months old. The same dyads were assessed using the HOME inventory concurrently and Bayley Scales of Infant Development III (BSID-III) at 18 months of age. Mixed effects linear regression was used to examine associations between MORS-SF (explanatory variable) and HOME-IT, and the cognitive, language and motor domains of BSID-III (outcome variables). Results: 1273 dyads completed all assessments. For the motor and language BSID-III scales and for HOME-IT there were strong and positive associations with the MORS-SF warmth sub-scale, and strong and negative associations with the invasion sub-scale. Important but less strong associations were seen with the BSID-III cognitive scale. Evidence of interaction suggested that both are individually important for child development. Conclusions: This is the first time MORS-SF has been used in India where optimising responsive caregiving is of importance in supporting all children to reach their potential. It is also the first time that the tool has been used in relation to child development. MORS-SF could be a valuable addition to evaluation in early childhood development.

Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr-/- mice.

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr-/- mice, a model of FH. Compared to hypercholesterolemic Ldlr-/- mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr-/- mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.

Synthesis of tetranor-PGE1: a urinary metabolite of prostaglandins E1 and E2.

Prostaglandin E2 is produced in response to inflammation, often associated with human disease. As prostaglandins are rapidly metabolized, quantification of end urinary metabolites depend on chemical synthesis of isotopically labeled standards to support metabolite quantification. A concise synthesis of tetranor-PGE1 is described including a late stage incorporation of an isotopically labeled side-chain.

Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial.

BACKGROUND: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer's disease. METHODS: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. RESULTS: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10-3.27 h, and an accumulation ratio of 1.38-1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. CONCLUSIONS: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. TRIAL REGISTRATION: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

First-in-human study assessing safety, tolerability, and pharmacokinetics of 2-hydroxybenzylamine acetate, a selective dicarbonyl electrophile scavenger, in healthy volunteers.

BACKGROUND: 2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer's disease. METHODS: In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. RESULTS: Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1-2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. CONCLUSIONS: 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03176940).

In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate.

2-hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive γ-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2-HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA.

Transcultural adaptation to the Brazilian Portuguese of the Postpartum Bonding Questionnaire for assessing the postpartum bond between mother and baby.

The establishment of the bond between mother and baby in the postpartum period is important for ensuring the physical and psychological health of both. This short communication reports the first phase of the cross-cultural translation and adaptation to the Brazilian context of the Postpartum Bonding Questionnaire (PBQ). Four aspects of equivalence between the original scale and the Portuguese version were evaluated: the conceptual, semantic, operational and item equivalences. Literature review, the study of PBQ history, translation, expert evaluation, back-translation and pretests involving 30 mothers with children aging up to 7 months using a primary healthcare unit were conducted. Each step demonstrated the need for adjustments, which were made during the adaptation process. At the end of the study, a version of PBQ in Brazilian Portuguese equivalent to the original one was obtained, offering promise for national studies on the mother-baby bond, and its influence on health, and for use in health services.

Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.

Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration: NCT01641289.

Transcultural adaptation to the Brazilian Portuguese of the Postpartum Bonding Questionnaire for assessing the postpartum bond between mother and baby / Adaptação transcultural para o português do Brasil do Postpartum Bonding Questionnaire para avaliação do vínculo no pós-parto entre mãe e bebê / Adaptación transcultural al portugués brasileño del Postpartum Bonding Questionnaire para evaluar el vínculo en el posparto entre la madre y el bebé

Abstract: The establishment of the bond between mother and baby in the postpartum period is important for ensuring the physical and psychological health of both. This short communication reports the first phase of the cross-cultural translation and adaptation to the Brazilian context of the Postpartum Bonding Questionnaire (PBQ). Four aspects of equivalence between the original scale and the Portuguese version were evaluated: the conceptual, semantic, operational and item equivalences. Literature review, the study of PBQ history, translation, expert evaluation, back-translation and pretests involving 30 mothers with children aging up to 7 months using a primary healthcare unit were conducted. Each step demonstrated the need for adjustments, which were made during the adaptation process. At the end of the study, a version of PBQ in Brazilian Portuguese equivalent to the original one was obtained, offering promise for national studies on the mother-baby bond, and its influence on health, and for use in health services.

Resumo: O estabelecimento do vínculo entre mãe e bebê no período pós-parto é importante para garantir a saúde física e psicológica de ambos. Esta artigo relata a primeira fase da tradução e adaptação transcultural ao contexto brasileiro do Postpartum Bonding Questionnaire (PBQ). Quatro aspectos de equivalência entre a escala original e a versão em português foram avaliados: as equivalências conceitual, semântica, operacional e de item. Foi realizada revisão de literatura, estudo da história do PBQ, tradução, avaliação por especialistas, retrotradução e pré-testes envolvendo 30 mães com crianças com até sete meses de idade, que utilizaram unidades básicas de saúde. Cada passo demonstrou a necessidade de ajustes, que foram feitos durante o processo de adaptação. Ao final do estudo, obteve-se uma versão do PBQ em português do Brasil equivalente à original, possibilitando estudos nacionais sobre o vínculo mãe-bebê e sua influência na saúde e uso nos serviços de saúde.

Resumen: El establecimiento del vínculo entre la madre y el bebé en el período posparto es importante para garantizar la salud física y psicológica de ambos. Este artículo informa la primera fase de la traducción y adaptación transcultural al contexto brasileño del Postpartum Bonding Questionnaire (PBQ). Se evaluaron cuatro aspectos de la equivalencia entre la escala original y la versión en portugués: las equivalencias conceptuales, semánticas, operacionales y de ítem. Se realizó una revisión de la literatura, el estudio de la historia de PBQ, la traducción, la evaluación de expertos, la retrotraducción y los exámenes previos que involucraron a 30 madres con niños de hasta siete meses que usaban una unidad de salud primaria. Cada paso demostró la necesidad de ajustes, que se realizaron durante el proceso de adaptación. Al final del estudio, se obtuvo una versión de PBQ en portugués de Brasil equivalente a la original, permitiendo estudios nacionales sobre el vínculo madre-bebé, y su influencia en la salud, y para su uso en los servicios de salud.

Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.

Triamterene Enhances the Blood Pressure Lowering Effect of Hydrochlorothiazide in Patients with Hypertension.

BACKGROUND: Triamterene, because of its potassium-sparing properties, is frequently used in combination with hydrochlorothiazide (HCTZ) to treat patients with hypertension. By inhibiting the epithelial sodium channel (ENaC) in the cortical collecting duct, triamterene reduces potassium secretion, thus reducing the risk of hypokalemia. Whether triamterene has an independent effect on blood pressure (BP) has not been well studied. OBJECTIVE: To determine if triamterene provides an effect to further lower BP in patients treated with HCTZ. DESIGN: We conducted an observational study using electronic medical record data from the Indiana Network for Patient Care. Participants were 17,291 patients with the diagnosis of hypertension between 2004 and 2012. MAIN MEASURES: BP was the primary outcome. We compared the BP between patients who were taking HCTZ, with and without triamterene, either alone or in combination with other antihypertensive medications, by using a propensity score analysis. For each medication combination, we estimated the propensity score (i.e., probability) of a patient receiving triamterene using a logistic regression model. Patients with similar propensity scores were stratified into subclasses and BP was compared between those taking triamterene or not within each subclass; the effect of triamterene was then assessed by combining BP differences estimated from all subclasses. KEY RESULTS: The mean systolic BP in the triamterene + HCTZ group was 3.8 mmHg lower than in the HCTZ only group (p < 0.0001); systolic BP was similarly lower for patients taking triamterene with other medication combinations. Systolic BP reduction was consistently observed for different medication combinations. The range of systolic BP reduction was between 1 and 4 mm Hg, depending on the concurrently used medications. CONCLUSIONS: In the present study, triamterene was found to enhance the effect of HCTZ to lower BP. In addition to its potassium-sparing action, triamterene's ability to lower BP should also be considered.

Modification of platelet proteins by malondialdehyde: prevention by dicarbonyl scavengers.

The thromboxane synthase converts prostaglandin H(2) to thromboxane A(2) and malondialdehyde (MDA) in approximately equimolar amounts. A reactive dicarbonyl, MDA forms covalent adducts of amino groups, including the ε-amine of lysine, but the importance of this reaction in platelets was unknown. Utilizing a novel LC/MS/MS method for analysis of one of the MDA adducts, the dilysyl-MDA cross-link, we demonstrated that dilysyl-MDA cross-links in human platelets are formed following platelet activation via the cyclooxygenase (COX)-1/thromboxane synthase pathway. Salicylamine and analogs of salicylamine were shown to react with MDA preferentially, thereby preventing formation of lysine adducts. Dilysyl-MDA cross-links were measured in two diseases known to be associated with increased platelet activation. Levels of platelet dilysyl-MDA cross-links were increased by 2-fold in metabolic syndrome relative to healthy subjects, and by 1.9-fold in sickle cell disease (SCD). In patients with SCD, the reduction of platelet dilysyl-MDA cross-links following administration of nonsteroidal anti-inflammatory drug provided evidence that MDA modifications of platelet proteins in this disease are derived from the COX pathway. In summary, MDA adducts of platelet proteins that cross-link lysines are formed on platelet activation and are increased in diseases associated with platelet activation. These protein modifications can be prevented by salicylamine-related scavengers.

Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.

OBJECTIVES: This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. DESIGN: Single-center, randomized, double-blind, placebo-controlled phase II trial. SETTING: Medical ICU in a tertiary, academic medical center. PATIENTS: Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin. INTERVENTIONS: Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. MEASUREMENTS AND MAIN RESULTS: F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599). CONCLUSIONS: In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.

Protein modification by adenine propenal.

Base propenals are products of the reaction of DNA with oxidants such as peroxynitrite and bleomycin. The most reactive base propenal, adenine propenal, is mutagenic in Escherichia coli and reacts with DNA to form covalent adducts; however, the reaction of adenine propenal with protein has not yet been investigated. A survey of the reaction of adenine propenal with amino acids revealed that lysine and cysteine form adducts, whereas histidine and arginine do not. N(ε)-Oxopropenyllysine, a lysine-lysine cross-link, and S-oxopropenyl cysteine are the major products. Comprehensive profiling of the reaction of adenine propenal with human serum albumin and the DNA repair protein, XPA, revealed that the only stable adduct is N(ε)-oxopropenyllysine. The most reactive sites for modification in human albumin are K190 and K351. Three sites of modification of XPA are in the DNA-binding domain, and two sites are subject to regulatory acetylation. Modification by adenine propenal dramatically reduces XPA's ability to bind to a DNA substrate.

Levuglandin forms adducts with histone h4 in a cyclooxygenase-2-dependent manner, altering its interaction with DNA.

Inflammation and subsequent cyclooxygenase-2 (COX-2) activity has long been linked with the development of cancer, although little is known about any epigenetic effects of COX-2. A product of COX-2 activation, levuglandin (LG) quickly forms covalent bonds with nearby primary amines, such as those in lysine, which leads to LG-protein adducts. Here, we demonstrate that COX-2 activity causes LG-histone adducts in cultured cells and liver tissue, detectable through LC-MS, with the highest incidence in histone H4. Adduction is blocked by a γ-ketoaldehyde scavenger, which has no effect on COX-2 activity as measured by PGE2 production. Formation of the LG-histone adduct is associated with an increased histone solubility in NaCl, indicating destabilization of the nucleosome structure; this is also reversed with scavenger treatment. These data demonstrate that COX-2 activity can cause histone adduction and loosening of the nucleosome complex, which could lead to altered transcription and contribute to carcinogenesis.