Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies. Dose-dependent treatment effects were observed in some biomarkers. No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations

Effects of Italian Smoking Regulation on Rates of Hospital Admission for Acute Coronary Events: A Country-Wide Study

BACKGROUND: Several studies have reported a reduction in acute coronary events (ACEs) in the general population after the enforcement of smoking regulations, although there is uncertainty concerning the magnitude of the effect of such interventions. We conducted a country-wide evaluation of the health effects of the introduction of a smoking ban in public places, using data on hospital admissions for ACEs from the Italian population after the implementation of a national smoking regulation in January 2005. METHODS AND FINDINGS: Rates of admission for ACEs in the 20 Italian regions from January 2002 to November 2006 were analysed using mixed-effect regression models that allowed for long-term trends and seasonality. Standard methods for interrupted time-series were adopted to assess the immediate and gradual effects of the smoking ban. Effect modification by age was investigated, with the assumption that exposure to passive smoking in public places would be greater among young people. In total, 936,519 hospital admissions for ACEs occurred in the Italian population during the study period. A 4% reduction in hospital admissions for ACEs among persons aged less than 70 years was evident after the introduction of the ban (Rate Ratio [RR], 0.96; 95% Confidence Interval [CI], 0.95-0.98). No effect was found among persons aged at least 70 years (RR 1.00; 95% CI 0.99-1.02). Effect modification by age was further suggested by analyses using narrower age categories. CONCLUSIONS: Smoke-free policies can constitute a simple and inexpensive intervention for the prevention of cardiovascular diseases and thus should be included in prevention programmes

Risk and Cooperation: Managing Hazardous Fuel in Mixed Ownership Landscapes

Managing natural processes at the landscape scale to promote forest health is important, especially in the case of wildfire, where the ability of a landowner to protect his or her individual parcel is constrained by conditions on neighboring ownerships. However, management at a landscape scale is also challenging because it requires cooperation on plans and actions that cross ownership boundaries. Cooperation depends on people’s beliefs and norms about reciprocity and perceptions of the risks and benefits of interacting with others. Using logistic regression tests on mail survey data and qualitative analysis of interviews with landowners, we examined the relationship between perceived wildfire risk and cooperation in the management of hazardous fuel by nonindustrial private forest (NIPF) owners in fire-prone landscapes of eastern Oregon. We found that NIPF owners who perceived a risk of wildfire to their properties, and perceived that conditions on nearby public forestlands contributed to this risk, were more likely to have cooperated with public agencies in the past to reduce fire risk than owners who did not perceive a risk of wildfire to their properties. Wildfire risk perception was not associated with past cooperation among NIPF owners. The greater social barriers to private–private cooperation than to private–public cooperation, and perceptions of more hazardous conditions on public compared with private forestlands may explain this difference. Owners expressed a strong willingness to cooperate with others in future cross-boundary efforts to reduce fire risk, however. We explore barriers to cooperative forest management across ownerships, and identify models of cooperation that hold potential for future collective action to reduce wildfire risk

Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis.

Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1α (HIF1α) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1α-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis

The effects of spatially heterogeneous prey distributions on detection patterns in foraging seabirds

Many attempts to relate animal foraging patterns to landscape heterogeneity are focused on the analysis of foragers movements. Resource detection patterns in space and time are not commonly studied, yet they are tightly coupled to landscape properties and add relevant information on foraging behavior. By exploring simple foraging models in unpredictable environments we show that the distribution of intervals between detected prey (detection statistics)is mostly determined by the spatial structure of the prey field and essentially distinct from predator displacement statistics. Detections are expected to be Poissonian in uniform random environments for markedly different foraging movements (e.g. L\'evy and ballistic). This prediction is supported by data on the time intervals between diving events on short-range foraging seabirds such as the thick-billed murre ({\it Uria lomvia}). However, Poissonian detection statistics is not observed in long-range seabirds such as the wandering albatross ({\it Diomedea exulans}) due to the fractal nature of the prey field, covering a wide range of spatial scales. For this scenario, models of fractal prey fields induce non-Poissonian patterns of detection in good agreement with two albatross data sets. We find that the specific shape of the distribution of time intervals between prey detection is mainly driven by meso and submeso-scale landscape structures and depends little on the forager strategy or behavioral responses.Comment: Submitted first to PLoS-ONE on 26/9/2011. Final version published on 14/04/201

Atlantic Leatherback Migratory Paths and Temporary Residence Areas

BACKGROUND: Sea turtles are long-distance migrants with considerable behavioural plasticity in terms of migratory patterns, habitat use and foraging sites within and among populations. However, for the most widely migrating turtle, the leatherback turtle Dermochelys coriacea, studies combining data from individuals of different populations are uncommon. Such studies are however critical to better understand intra- and inter-population variability and take it into account in the implementation of conservation strategies of this critically endangered species. Here, we investigated the movements and diving behaviour of 16 Atlantic leatherback turtles from three different nesting sites and one foraging site during their post-breeding migration to assess the potential determinants of intra- and inter-population variability in migratory patterns. METHODOLOGY/PRINCIPAL FINDINGS: Using satellite-derived behavioural and oceanographic data, we show that turtles used Temporary Residence Areas (TRAs) distributed all around the Atlantic Ocean: 9 in the neritic domain and 13 in the oceanic domain. These TRAs did not share a common oceanographic determinant but on the contrary were associated with mesoscale surface oceanographic features of different types (i.e., altimetric features and/or surface chlorophyll a concentration). Conversely, turtles exhibited relatively similar horizontal and vertical behaviours when in TRAs (i.e., slow swimming velocity/sinuous path/shallow dives) suggesting foraging activity in these productive regions. Migratory paths and TRAs distribution showed interesting similarities with the trajectories of passive satellite-tracked drifters, suggesting that the general dispersion pattern of adults from the nesting sites may reflect the extent of passive dispersion initially experienced by hatchlings. CONCLUSIONS/SIGNIFICANCE: Intra- and inter-population behavioural variability may therefore be linked with initial hatchling drift scenarios and be highly influenced by environmental conditions. This high degree of behavioural plasticity in Atlantic leatherback turtles makes species-targeted conservation strategies challenging and stresses the need for a larger dataset (>100 individuals) for providing general recommendations in terms of conservation

Activation of transcription factors by extracellular nucleotides in immune and related cell types

Extracellular nucleotides, acting through P2 receptors, can regulate gene expression via intracellular signaling pathways that control the activity of transcription factors. Relatively little is known about the activation of transcription factors by nucleotides in immune cells. The NF-κB family of transcription factors is critical for many immune and inflammatory responses. Nucleotides released from damaged or stressed cells can act alone through certain P2 receptors to alter NF-κB activity or they can enhance responses induced by pathogen-associated molecules such as LPS. Nucleotides have also been shown to regulate the activity of other transcription factors (AP-1, NFAT, CREB and STAT) in immune and related cell types. Here, we provide an overview of transcription factors shown to be activated by nucleotides in immune cells, and describe what is known about their mechanisms of activation and potential functions. Furthermore, we propose areas for future work in this new and expanding field