Background. Selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with ...neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at a body surface area (BSA)-based dose of 25 mg/m2 twice daily. The objective of this population pharmacokinetic analysis was to evaluate ethnic sensitivity in the pharmacokinetics of selumetinib and N-desmethyl selumetinib between Japanese and non-Japanese pediatric patients. Methods. This population pharmacokinetic analysis was based on data from 80 pediatric patients enrolled in two clinical trials, one conducted in Japan and one conducted in the United States, comprising 12 Japanese participants and 68 non-Japanese participants. Both clinical trials used BSA-based dosing schemes. A two-compartment model with first-order elimination and sequential zero-order and first-order delayed absorption for selumetinib, combined with a one-compartment model with first-order elimination for N-desmethyl selumetinib, was used for this analysis. Ethnic sensitivity in pharmacokinetics was evaluated by covariate modeling and comparison of model-predicted exposures. Results. Covariate modeling showed that BSA had a clinically relevant impact on the pharmacokinetics of selumetinib. None of the other investigated covariates, such as race, had a significant impact. The predicted exposure in Japanese and non-Japanese patients showed a considerably overlapping distribution, and no clinically relevant difference in exposure was apparent. Conclusions. These findings support the use of the same BSA-based dosing regimen for Japanese and non-Japanese pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. Subsequent to this analysis, selumetinib was approved at the BSA-based dose of 25 mg/m2 in Japan, which is consistent with the recommended dosage and administration in other regions and countries. This analysis used data from trial registered with NCT04495127, and NCT01362803.
Chronologies of earlywood vessel size of ring-porous trees contain valuable ecological information, but long preparation procedures limit their application in ecological studies. Recent and fast ...techniques for wood surface preparation combined with automated image analysis are reducing the work needed to build chronologies, but might also entail measurement inaccuracy. In this study, we aim to evaluate the effect of a possible efficiency-accuracy trade-off on ecological signal strength. To this end, we compare measurements of mean vessel area from two recent and fast procedures carried out on sanded wood surfaces with a reference procedure based on an accurate survey from thin sections. Measurements were performed on increment cores of 15 sessile oaks (Quercus petraea (Mattuschka) Liebl.) for the period 1956-2006. Dissimilarities in results with the reference procedure were quantified and evaluated. Our data show that the workload can be reduced by more than 20-fold when using the highly automated procedure. Signal weakening caused by measurement errors is negligible for vessels >6,000 μm² and can be easily compensated by increasing the sample size. Manual correction of misrecognized vessels hardly reduced this error further. The new procedures constitute a major step towards an efficient and accurate analysis of earlywood vessel chronologies of ring-porous tree species.
Ante la falta de regulación constitucional expresa sobre el régimen de las posibles alteraciones territoriales del mapa autonómico, la doctrina mayoritaria, apoyada fundamentalmente en la STC ...99/1986, ha venido defendiendo una interpretación muy amplia de la remisión que el art. 147.2.b de la Constitución hace a los estatutos de autonomía para realizar la delimitación del territorio autonómico. En este trabajo se justifica por qué esa habilitación a los estatutos no es suficiente para que, a través de la reforma de los mismos, se lleve a cabo la creación de una nueva comunidad autónoma a partir de la integración de otras preexistentes.
•Relations between the timings of budburst and wood formation were established.•Full leaf development requires new functional earlywood vessels.•Spring temperature modifies the onset of primary and ...secondary growth differently.•Synchronicity between wood and leaf development can be modified by temperature.
We investigated how temperature patterns affect cambial activity and leaf phenology of oak across a wide range of natural woodlands at its southwestern distribution boundary. Understanding the climatic control of wood formation in dominant species is very relevant to infer tree responses to ongoing environmental changes and their impact on the carbon cycle.
We selected nine sites along two elevation gradients from the coastline in northwestern Iberia, and sampled ten trees per site biweekly during 2012 and 2013. Leaf and cambial phenological phases were related to mean air temperature for 10–60 day running periods along the year to identify the most relevant time windows for cambium and leaf phenophases, and the relationships among them.
The first earlywood vessels expanded before the appearance of small leaves, and subsequently underwent maturation to meet water requirements for full leaf unfolding. The advance or delay of cambial reactivation and budburst varied among sites and years modulated by spring temperature, and were respectively maximized by maximum and minimum values.
Temperature can modify the onset of early phenophases of primary and secondary growth differently, and also the synchronicity between them. However, the maturation of the first earlywood vessels is necessary to undergo full leaf extension.
• Wood anatomical features measured in dated tree rings have often proven to be of ecological value. However, little is known about the suitability and power of such measurements studied in a ...year-to-year basis as is done in dendrochronology. • The present work is based on a comparative analysis of 60 dated time-series of earlywood features of chestnut (Castanea sativa) grown in the climatic context of the Southern part of the Swiss Alps. • It has been shown that the earlywood vessel area is a suitable ecological indicator. This variable, although not very sensitive, contains environmental information that is different from that stored in all other ring-width and earlywood features we considered. The vessel size is mainly related to the temperature during two physiologically crucial periods for vessel growth: the end of the previous vegetation period (during reserve storage) and the onset of cambial activity (during cell division and vessel differentiation). • Our work shows that the mean vessel size of the ring-porous chestnut contains ecophysiological information that can be used for research in dendrochronology.
The major objective of in vitro-in vivo correlations is to be able to use in vitro data to predict in vivo performance serving as a surrogate for an in vivo bioavailability test and to support ...biowaivers. Therefore, the aims of this review are: (i) to clarify the factors involved during bio-predictive dissolution method development; and (ii) the elements that may affect the mathematical analysis in order to exploit all information available. This article covers the basic aspects of dissolution media and apparatus used in the development of in vivo predictive dissolution methods, including the latest proposals in this field as well as the summary of the mathematical methods for establishing the in vitro-in vivo relationship and their scope and limitations. The incorporation of physiological relevant factors in the in vitro dissolution method is essential to get accurate in vivo predictions. Standard quality control dissolution methods do not necessarily reflect the in vivo behavior, so they rarely are useful for predicting in vivo performance. The combination of physiological based dissolution methods with physiological-based pharmacokinetics models incorporating gastrointestinal variables will lead to robust tools for drug and formulation development, nevertheless their regulatory use for biowaiver application still require harmonization of the mathematical methods proposed and more detailed recommendations about the procedures for setting up dissolution specifications.
Non-structural carbohydrates (NSC) play a central role in the construction and maintenance of a tree's vascular system, but feedbacks between the NSC status of trees and wood formation are not fully ...understood. We aimed to evaluate multiple dependencies among wood anatomy, winter NSC, and phenology for coexisting temperate (Quercus robur) and sub-Mediterranean (Q. pyrenaica) oaks along a water-availability gradient in the NW Iberian Peninsula. Sapwood NSC concentrations were quantified at three sites in December 2012 (N = 240). Leaf phenology and wood anatomy were surveyed in 2013. Structural equation modelling was used to analyse the interplay among hydraulic diameter (Dh), winter NSC, budburst date, and earlywood vessel production (EVP), while the effect of Dh and EVP on latewood width was assessed by using a mixed-effects model. NSC and wood production increased under drier conditions for both species. Q. robur showed a narrower Dh and lower soluble sugar (SS) concentration (3.88–5.08 % dry matter) than Q. pyrenaica (4.06–5.57 % dry matter), but Q. robur exhibited larger EVP and wider latewood (1403 µm) than Q. pyrenaica (667 µm). Stem diameter and Dh had a positive effect on SS concentrations, which were related to an earlier leaf flushing in both species. Sapwood sugar content appeared to limit EVP exclusively in Q. pyrenaica. In turn, Dh and EVP were found to be key predictors of latewood growth. Our results confirm that sapwood SS concentrations are involved in modulating growth resumption and xylem production in spring. Q. pyrenaica exhibited a tighter control of carbohydrate allocation to wood formation than Q. robur, which would play a role in protecting against environmental stress in the sub-Mediterranean area.
•Positive and significant relationship between the interannual variability and the secondary growth.•Similar average correlations among all different forest types.•Maximum correlations found between ...NDVI and tree-ring growth are recorded considering cumulative NDVI values.•Temporal lags may be expected due to particular physiological processes.
This study links tree-ring growth and gross primary production for a variety of forest types under different environmental conditions across Spain. NOAA-AVHRR satellite imagery data were combined with dendrochronological records and climate data at a fine spatial resolution (1.21 km2) to analyze the interannual variability of tree-ring growth and vegetation activity for different forest biomes from 1981 to 2015. Specifically, we assessed the links between tree-ring width indices (TRWi), the Normalized Difference Vegetation Index (NDVI) and a variety of environmental conditions, represented by climatic variables (air temperature, precipitation, evapotranspiration and water balance) and elevation. The impact of these variables on tree growth was assessed by means of the Predictive Discriminant Analysis (PDA). Results reveal a general positive and significant relationship between inter-annual variability of the NDVI at a high spatial resolution (1.21 km2) and tree-ring growth. Maximum correlations between NDVI and tree-ring growth were recorded when cumulative NDVI values were considered, in some cases covering long time periods (6–10 months), suggesting that tree growth is mainly related to Gross Primary Production (GPP) at annual scale. The relationship between tree-ring growth and inter-annual variability of the NDVI, however, strongly varies between forest types and environmental conditions.
Tree rings are natural archives of climate and environmental information with a yearly resolution. Indeed, wood anatomical, chemical, and other properties of tree rings are a synthesis of several ...intrinsic and external factors, and their interaction during tree growth. In particular, Intra-Annual Density Fluctuations (IADFs) can be considered as tree-ring anomalies that can be used to better understand tree growth and to reconstruct past climate conditions with intra-annual resolution. However, the ecophysiological processes behind IADF formation, as well as their functional impact, remain unclear. Are IADFs resulting from a prompt adjustment to fluctuations in environmental conditions to avoid stressful conditions and/or to take advantage from favorable conditions? In this paper we discuss: (1) the influence of climatic factors on the formation of IADFs; (2) the occurrence of IADFs in different species and environments; (3) the potential of new approaches to study IADFs and identify their triggering factors. Our final aim is to underscore the advantages offered by network analyses of data and the importance of high-resolution measurements to gain insight into IADFs formation processes and their relations with climatic conditions, including extreme weather events.
Macaronesian laurel forests are the only remnants of a subtropical palaeoecosystem dominant during the Tertiary in Europe and northern Africa. These biodiverse ecosystems are restricted to cloudy and ...temperate insular environments in the North Atlantic Ocean. Due to their reduced distribution area, these forests are particularly vulnerable to anthropogenic disturbances and changes in climatic conditions. The assessment of laurel forest trees’ response to climate variation by dendrochronological methods is limited because it was assumed that the lack of marked seasonality would prevent the formation of distinct annual tree rings. The aims of this study were to identify the presence of annual growth rings and to assess the dendrochronological potential of the most representative tree species from laurel forests in Tenerife, Canary Islands. We sampled increment cores from 498 trees of 12 species in two well-preserved forests in Tenerife Island. We evaluated tree-ring boundary distinctness, dating potential, and sensitivity of tree-ring growth to climate and, particularly, to drought occurrence. Eight species showed clear tree-ring boundaries, but synchronic annual tree rings and robust tree-ring chronologies were only obtained for Laurus novocanariensis, Ilex perado subsp. platyphylla, Persea indica and Picconia excelsa, a third of the studied species. Tree-ring width depended on water balance and drought occurrence, showing sharp reductions in growth in the face of decreased water availability, a response that was consistent among species and sites. Inter-annual tree-ring width variation was directly dependent on rainfall input in the humid period, from previous October to current April. The four negative pointer years 1995, 1999, 2008 and 2012 corresponded to severe drought events in the study area. This study gives the first assessment of dendrochronological potential and tree-ring climate sensitivity of tree species from the Tenerife laurel forest, which opens new research avenues for dendroecological studies in Macaronesian laurel forests.
•We characterized the tree-ring anatomy of twelve species from Tenerife Island.•We obtained robust chronologies for four tree species.•Radial growth variation directly depended on rainfall input during the humid period.•Negative pointer years matched drought events.•Climate sensitivity of growth was consistent across species and sites.
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