Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence

Study of several varieties of tree crowns on different rootstocks of mango (Mangifera indica L.)

O objetivo deste trabalho foi verificar a interferência copa x porta-enxerto no desenvolvimento da mangueira. As alturas e os diâmetros das copas foram tomadas uma vez em 1981, quando as 210 plantas atingiram 15 anos de idade. As variedades de copas estudadas foram as seguintes: Extrema, Oliveira Neto, Carlota, Imperial, Pahiri e Bourbon. Os porta-enxertos utilizados foram Espada, Extrema, Olivara Neto, Carlota, Coco, Pahiri e Bourbon. Os dados foram analisados e a comparação das médias foi feita através do teste de Tukey em nível de 5% de probabilidade. O estudo mostrou que as variedades de copa, Olivara Neto, Extrema e Bourbon atingiram uma altura e um diâmetro maior que as demais variedades.The aim of this paper was to investigate the influence of the combination tree crown + rootstock on mango tree performance. The trees were selected according to height and crown diameter, measured once in 1981, using 210 trees, 15 years old at the beginning of the experiment. The Extrema, Espada, Oliveira Neto, Carlota, Bourbon, Coco and Pahiri varieties were used as rootstock and Extrema, Pahiri, Imperial, Oliveira Neto, Cariota e Bourbon were utilized as scions for tree crown development. Data were analysed by classical statistics, comparing means through the Tukey test, at a probability level of 5%. The crowns Oliveira Neto, Extrema e Bourbon showed the highest heights and diametres

A single synonymous mutation determines the phosphorylation and stability of the nascent protein

p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein

Early Adoption of an Improved Household Energy System in Urban Rwanda

Cooking with solid fuels and inefficient cookstoves has adverse consequences for health, environment, and human well-being. Despite the promise of improved cookstoves to reduce these impacts, adoption rates are relatively low. Using a 2-wave sample of 144 households from the baseline and first midline of an ongoing 4-year randomized controlled trial in Rwanda, we analyze the drivers and associations of early adoption of a household energy intervention marketed by a private sector firm. Households sign an annual contract to purchase sustainably produced biomass pellets and lease a fan micro-gasification cookstove with verified emissions reductions in laboratory settings. Using difference-in-differences and fixed effects estimation techniques, we examine the association between take-up of the improved cooking system and household fuel expenditures, health outcomes, and time use for primary cooks. Thirty percent of households adopted the pellet and improved cookstove system. Adopting households had more assets, lower per capita total expenditures and cooking fuel expenditures, and higher per capita hygiene expenditures. Households with married household heads and female cooks were significantly more likely to adopt. Adjusting for confounders, we find significant reduction in primary cooks’ systolic blood pressure, self-reported prevalence of shortness of breath, an indicator of respiratory illness, time spent cooking, and household expenditures on charcoal. Our findings have implications for marketing of future clean fuel and improved cookstove programs in urban settings or where stoves and fuel are purchased. Analysis of follow-up surveys will allow for estimation of long-term impacts of adoption of interventions involving pellets and fan micro-gasification cookstoves

Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue

Can sexual selection drive female life histories? A comparative study on Galliform birds

Sexual selection is an important driver of many of the most spectacular morphological traits that we find in the animal kingdom (for example see Andersson, 1994). As such, sexual selection is most often emphasized as