A preliminary investigation on the influence of flavonoids on ethyl glucuronide formation

Abstract Aims: A large variation of the formation of ethyl glucuronide (EtG) which is a minor metabolite of ethanol has been observed in man. At present there is only a single investigation on glucuronosyltransferases (UGT) responsible for catalyzing EtG formation whereas a possible influence of nutritional components on EtG formation has not been addressed at all. Methods: Following optimization of the substrate concentration, incubation conditions such as buffer and time, as well as isolation of EtG from the incubation mixture, recombinant UGT enzymes (UGT 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B10, 2B15) were screened for their activity towards ethanol. Subsequently, quercetin and kaempferol were chosen to study their possible influence on the glucuronidation of ethanol for UGT1A1, 1A3 and UGT1A9. Analysis of EtG formation was performed by LC-MS/MS following solid phase extraction. EtG-d 5 was used as the internal standard. For inhibition experiments, EtG formation was determined after addition of kaempferol and quercetin in different concentrations to the incubation mixture to determine the half maximum inhibitory constants (IC 50 ). Results: Optimization of both, the incubation and isolation procedures resulted in a significant decrease of matrix effects. EtG was formed by all enzymes under investigation at variable rates ranging from 0.79 -10.41 pmol/min/mg at 50 mM ethanol and 0.95-12.9 pmol/mg/min at 200 mM ethanol. Respective kinetics followed the Michaelis-Menten model so that the Michaelis-Menten constant K m and the maximum velocity V max values could be calculated. Both flavonoids reduced formation of EtG, irrespective of the enzyme involved. The IC 50 -values ranged from 3.04 µM quercetin for UGT1A1 to 38.47 µM kaempferol for UGT1A9. Conclusions: Formation of EtG from ethanol is catalyzed by multiple UGT isoforms. In addition, co-incubation affected the glucuronidation rate, irrespective of the particular enzyme. It seems that nutritional components will influence conversion of ethanol to EtG which may partly explain its variable formation in man

Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-Resistant Prostate Cancer Clinical Trial

IMPORTANCE Standard adverse event (AE) reporting in oncology clinical trials has historically relied on clinician grading, which prior research has shown can lead to underestimation of rates of symptomatic AEs. Industry sponsors are beginning to implement in trials the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), which was developed to allow patients to self-report symptomatic AEs and improve the quality of symptomatic AE detection. OBJECTIVES To evaluate the feasibility of implementing PRO-CTCAE in a prespecified correlative analysis of the phase 3 COMET-2 trial and enumerate statistically significant between-group differences in symptomatic AEs using PRO-CTCAE and the CTCAE. DESIGN, SETTING, AND PARTICIPANTS This correlative study of 119 men in the randomized, double-blind, placebo-controlled phase 3 COMET-2 trial with metastatic castration-resistant prostate cancer who had undergone at least 2 prior lines of systemic treatment was conducted from March 2012 to July 2014. Participants completed PRO-CTCAE items using an automated telephone system from home prior to treatment and every 3 weeks during treatment. Statistical analysis was performed from May 2018 to June 2019. MAIN OUTCOMES AND MEASURES The proportion of patients who completed expected PRO-CTCAE self-reports was computed as a measure of feasibility. RESULTS Among the 119 men in the study (median age, 65 years [range, 44-80 years]), 534 of 587 (91.0%) expected PRO-CTCAE self-reports were completed, with consistently high rates of completion throughout participation. Rates of self-report adherence were similar between groups (cabozantinib s-maleate, 286 of 317 [90.2%]; and mitoxantrone hydrochloride-prednisone, 248 of 270 [91.9%]). Of 12 measured, patient-reported PRO-CTCAE symptomatic AEs, 4 reached statistical significance when comparing the proportion of patients with at least 1 postbaseline score greater than 0 between groups (differences ranged from 20.1% to 34.1% with higher proportions in the cabozantinib group; all P < .05), and use of a method for accounting for preexisting symptoms at baseline yielded 7 AEs with statistically significant differences between groups (differences ranged from 20.5%to 41.2%with higher proportions in the cabozantinib group; all P < .05). In the same analysis using investigator-reported CTCAE data, no statistically significant differences were found between groups for any symptomatic AEs. CONCLUSIONS AND RELEVANCE PRO-CTCAE data collection was feasible and improved the accuracy of symptomatic AE detection in a phase 3 cancer trial. This analysis adds to mounting evidence of the feasibility and value of patient-reported AEs in oncology, which should be considered for inclusion in cancer trials that incorporate AE evaluation

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

<p>Abstract</p> <p>Background</p> <p>National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.</p> <p>Methods</p> <p>In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.</p> <p>Results</p> <p>Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.</p> <p>Conclusions</p> <p>Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.</p

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (n(NationMS) = 946, n(BIONAT) = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS

Evaluation des Verwaltungsmodernisierungsprozesses "Change²" der Stadt Mannheim

Die Stadt Mannheim hat 2008 einen Verwaltungsmodernisierungsprozess mit dem postulierten Ziel begonnen "eine der modernsten Stadtverwaltungen Deutschlands" bis zum Jahr 2013 zu werden. Dieser Prozess wurde durch das Deutsche Forschungsinstitut für öffentliche Verwaltung (FÖV) Speyer evaluiert. Bei der Evaluation wurde zum einen die rückblickende Bewertung des stattgefundenen Modernisierungsprozesses, zum anderen die mögliche Fortführung von CHANGE² ab dem Jahr 2014 in den Blick genommen

Comparison of weekly and daily recall of pain as an endpoint in a randomized phase 3 trial of cabozantinib for metastatic castration-resistant prostate cancer

10.1177/17407745211009547Clinical Trials184408-41

Aptitud combinatoria de cruzas intra e interespecíficas del género Sphaeralcea con potencial ornamental

El uso de recursos genéticos nativos ha sido escasamente explorado en Argentina. El género Sphaeralcea (Malvaceae), reúne especies nativas con características atractivas para la horticultura ornamental. Una condición necesaria para el mejoramiento de una especie vegetal es el conocimiento de la aptitud combinatoria entre y dentro de las especies. En este trabajo se evaluó la aptitud combinatoria de cruzas intra e interespecíficas para las especies S. australis, S. crispa, S. bonariensis y S. mendocina, determinando el porcentaje de germinación de semillas descendientes y la supervivencia de plántulas F1. Luego de la escarificación mecánica la germinación fue elevada, para descendientes intraespecíficos germinaron 373 semillas de un total de 537 y para descendientes interespecíficos germinaron 1098 de 1428 semillas. La supervivencia fue variable según cada combinación interespecífica, bajos valores (35% a 40%) cuando el parental femenino fue S. mendocina, intermedios (43% a 67%) cuando el parental femenino fue S. bonariensis y altos valores (73% a 100%) cuando el parental femenino fue S. australis. Con S. crispa como parental femenino la supervivencia varió entre 0% y 93%. Los F1 intraespecíficos de S. crispa y S. bonariensis tuvieron una supervivencia de alrededor del 50% y los F1 de S. australis y S. mendocina superior al 85%. Las especies de Sphaeralcea demostraron compatibilidad reproductiva entre ellas, esta es una condición fundamental a la hora de encarar estrategias de mejoramiento en el género.Fil: Monzón, María Paula. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Schwab, Gisela Elizabeth. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Ronconi, Sofía. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaFil: Gutierrez, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Marinangeli, Pablo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur. Departamento de Agronomía; ArgentinaXXXVIII Jornadas Argentinas de Botánica. Aunando saberesOro VerdeArgentinaSociedad Argentina de Botánic