Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

International audienceBACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody

Phenotypic Plasticity of Leaf Shape along a Temperature Gradient in Acer rubrum

Both phenotypic plasticity and genetic determination can be important for understanding how plants respond to environmental change. However, little is known about the plastic response of leaf teeth and leaf dissection to temperature. This gap is critical because these leaf traits are commonly used to reconstruct paleoclimate from fossils, and such studies tacitly assume that traits measured from fossils reflect the environment at the time of their deposition, even during periods of rapid climate change. We measured leaf size and shape in Acer rubrum derived from four seed sources with a broad temperature range and grown for two years in two gardens with contrasting climates (Rhode Island and Florida). Leaves in the Rhode Island garden have more teeth and are more highly dissected than leaves in Florida from the same seed source. Plasticity in these variables accounts for at least 6–19 % of the total variance, while genetic differences among ecotypes probably account for at most 69–87 %. This study highlights the role of phenotypic plasticity in leaf-climate relationships. We suggest that variables related to tooth count and leaf dissection in A. rubrum can respond quickly to climate change, which increases confidence in paleoclimate methods that use these variables

Tissue Clearing and Deep Imaging of the Kidney Using Confocal and Two-Photon Microscopy

Microscopic and macroscopic evaluation of biological tissues in three dimensions is becoming increasingly popular. This trend is coincident with the emergence of numerous tissue clearing strategies, and advancements in confocal and two-photon microscopy, enabling the study of intact organs and systems down to cellular and sub-cellular resolution. In this chapter, we describe a wholemount immunofluorescence technique for labeling structures in renal tissue. This technique combined with solvent-based tissue clearing and confocal imaging, with or without two-photon excitation, provides greater structural information than traditional sectioning and staining alone. Given the addition of paraffin embedding to our method, this hybrid protocol offers a powerful approach to combine confocal or two-photon findings with histological and further immunofluorescent analysis within the same tissue

Deformation-related volcanism in the Pacific Ocean linked to the Hawaiian-Emperor bend

Ocean islands, seamounts and volcanic ridges are thought to form above mantle plumes. Yet, this mechanism cannot explain many volcanic features on the Pacific Ocean floor and some might instead be caused by cracks in the oceanic crust linked to the reorganization of plate motions. A distinctive bend in the Hawaiian–Emperor volcanic chain has been linked to changes in the direction of motion of the Pacific Plate, movement of the Hawaiian plume, or a combination of both. However, these links are uncertain because there is no independent record that precisely dates tectonic events that affected the Pacific Plate. Here we analyse the geochemical characteristics of lava samples collected from the Musicians Ridges, lines of volcanic seamounts formed close to the Hawaiian–Emperor bend. We find that the geochemical signature of these lavas is unlike typical ocean island basalts and instead resembles mid-ocean ridge basalts. We infer that the seamounts are unrelated to mantle plume activity and instead formed in an extensional setting, due to deformation of the Pacific Plate. 40Ar/39Ar dating reveals that the Musicians Ridges formed during two time windows that bracket the time of formation of the Hawaiian–Emperor bend, 53–52 and 48–47 million years ago. We conclude that the Hawaiian–Emperor bend was formed by plate–mantle reorganization, potentially triggered by a series of subduction events at the Pacific Plate margins

Memory-encoding vibrations in a disconnecting air bubble

Many nonlinear processes, such as the propagation of waves over an ocean or the transmission of light pulses down an optical fibre1, are integrable in the sense that the dynamics has as many conserved quantities as there are independent variables. The result is a time evolution that retains a complete memory of the initial state. In contrast, the nonlinear dynamics near a finite-time singularity, in which physical quantities such as pressure or velocity diverge at a point in time, is believed to evolve towards a universal form, one independent of the initial state2. The break-up of a water drop in air3 or a viscous liquid inside an immiscible oil4,5 are processes that conform to this second scenario. These opposing scenarios collide in the nonlinearity produced by the formation of a finite-time singularity that is also integrable. We demonstrate here that the result is a novel dynamics with a dual character

Paleotemperature Proxies from Leaf Fossils Reinterpreted in Light of Evolutionary History

Present-day correlations between leaf physiognomic traits (shape and size) and climate are widely used to estimate paleoclimate using fossil floras. For example, leaf-margin analysis estimates paleotemperature using the modern relation of mean annual temperature (MAT) and the site-proportion of untoothed-leaf species (NT). This uniformitarian approach should provide accurate paleoclimate reconstructions under the core assumption that leaf-trait variation principally results from adaptive environmental convergence, and because variation is thus largely independent of phylogeny it should be constant through geologic time. Although much research acknowledges and investigates possible pitfalls in paleoclimate estimation based on leaf physiognomy, the core assumption has never been explicitly tested in a phylogenetic comparative framework. Combining an extant dataset of 21 leaf traits and temperature with a phylogenetic hypothesis for 569 species-site pairs at 17 sites, we found varying amounts of non-random phylogenetic signal in all traits. Phylogenetic vs. standard regressions generally support prevailing ideas that leaf-traits are adaptively responding to temperature, but wider confidence intervals, and shifts in slope and intercept, indicate an overall reduced ability to predict climate precisely due to the non-random phylogenetic signal. Notably, the modern-day relation of proportion of untoothed taxa with mean annual temperature (NT-MAT), central in paleotemperature inference, was greatly modified and reduced, indicating that the modern correlation primarily results from biogeographic history. Importantly, some tooth traits, such as number of teeth, had similar or steeper slopes after taking phylogeny into account, suggesting that leaf teeth display a pattern of exaptive evolution in higher latitudes. This study shows that the assumption of convergence required for precise, quantitative temperature estimates using present-day leaf traits is not supported by empirical evidence, and thus we have very low confidence in previously published, numerical paleotemperature estimates. However, interpreting qualitative changes in paleotemperature remains warranted, given certain conditions such as stratigraphically closely-spaced samples with floristic continuity

Shoulder muscle endurance: the development of a standardized and reliable protocol

<p>Abstract</p> <p>Background</p> <p>Shoulder muscle fatigue has been proposed as a possible link to explain the association between repetitive arm use and the development of rotator cuff disorders. To our knowledge, no standardized clinical endurance protocol has been developed to evaluate the effects of muscle fatigue on shoulder function. Such a test could improve clinical examination of individuals with shoulder disorders. Therefore, the purpose of this study was to establish a reliable protocol for objective assessment of shoulder muscle endurance.</p> <p>Methods</p> <p>An endurance protocol was developed on a stationary dynamometer (Biodex System 3). The endurance protocol was performed in isotonic mode with the resistance set at 50% of each subject's peak torque as measured for shoulder external (ER) and internal rotation (IR). Each subject performed 60 continuous repetitions of IR/ER rotation. The endurance protocol was performed by 36 healthy individuals on two separate occasions at least two days apart. Maximal isometric shoulder strength tests were performed before and after the fatigue protocol to evaluate the effects of the endurance protocol and its reliability. Paired <it>t</it>-tests were used to evaluate the reduction in shoulder strength due to the protocol, while intraclass correlation coefficients (ICC) and minimal detectable change (MDC) were used to evaluate its reliability.</p> <p>Results</p> <p>Maximal isometric strength was significantly decreased after the endurance protocol (<it>P </it>< 0.001). The total work performed during the last third of the protocol was significantly less than the first third of the protocol (P < 0.05). The test-retest reliability of the post-fatigue strength measures was excellent (ICC >0.84).</p> <p>Conclusions</p> <p>Changes in muscular performance observed during and after the muscular endurance protocol suggests that the protocol did result in muscular fatigue. Furthermore, this study established that the resultant effects of fatigue of the proposed isotonic protocol were reproducible over time. The protocol was performed without difficulty by all volunteers and took less than 10 minutes to perform, suggesting that it might be feasible for clinical practice. This protocol could be used to induce local muscular fatigue in order to evaluate the effects of fatigue on shoulder kinematics or to evaluate changes in shoulder muscle endurance following rehabilitation.</p

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

HIV Disease Impact on Mothers: What They Miss During Their Children’s Developmental Years

Adjusting to chronic illness is very complicated for families with children, as they are already faced with the challenge of development and childrearing. In this study, qualitative interviews were conducted with HIV positive mothers on a number of issues related to being an HIV positive mother raising young children. One topic of the interview was whether or not they felt that HIV had caused them to miss activities with their children while the children were growing up, what types of activities they had missed, the age of the child for each example, and how HIV had led to missing these activities. Interviews were conducted in 2008 with a random sample of 57 mothers being followed in a longitudinal assessment study. All study participants were English or Spanish speaking. Mean age was 44.1 (SD = 5.6) years; 47% were Latina; 35% African American; 11% White; and 7% other race. About 60% of the mothers disclosed that their HIV status had caused them to miss out on activities with their children while their children were growing up, ranging from daily care activities to major school and extra-curricular activities. Some mothers missed significant amounts of time with their children due to hospitalizations. In some cases mothers felt forced into a choice between mothering ability and their own health, including adherence to medications. Implications for the mothers and the children are discussed