Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis

Background/objective: The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) tanezumab administration in osteoarthritis (OA) patients. Materials and methods: Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient\u27s Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Results: Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in tanezumab groups ranged from -3.59 (0.26) to -3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (tanezumab 2.5 mg, n=11 [4.8%]; tanezumab 5 mg, n=8 [3.6%]; tanezumab 10 mg, n=15 [6.6%]). Conclusion: Preliminary results show similar efficacy and safety for both SC and IV administration of tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions

An Amazon Tipping Point: The Economic and Environmental Fallout

The Amazon biome, despite its resilience, is being pushed by unsustainable economic drivers towards an ecological tipping point where restoration to its previous state may no longer possible. This is the result of self-reinforcing interactions between deforestation, climate change and fire. In this paper, we develop scenarios that represent movement towards an Amazon tipping point and strategies to avert one. We assess the economic, natural capital and ecosystem services impacts of these scenarios using the Integrated Economic-Environmental Modeling (IEEM) Platform linked with high resolution spatial land use land cover change and ecosystem services modeling (IEEM+ESM). This paper’s main contributions are developing: (i) a framework for evaluating strategies to avert an Amazon tipping point based on their relative costs, benefits and trade-offs, and; (ii) a first approximation of the economic, natural capital and ecosystem services impacts of movement towards an Amazon tipping point, and evidence to build the economic case for strategies to avert it. We find that a conservative estimate of the cumulative regional cost through 2050 of an Amazon tipping point would be US$256.6 billion in Gross Domestic Product. Policies that would contribute to averting a tipping point, including strongly reducing deforestation, investing in climate-adapted agriculture, and improving fire management, would generate approximately US$339.3 billion in additional wealth. From a public investment perspective, the returns to implementing strategies for averting a tipping point would be US$29.5 billion. Quantifying the costs, benefits and trade-offs of policies to avert a tipping point in a transparent and replicable manner can pave the way for evidence-based approaches to support policy action focusing on the design of regional strategies for the Amazon biome and catalyze global cooperation and financing to enable their implementation.Centro de Estudios Distributivos, Laborales y Sociale

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Finding Homogeneity in Heterogeneity—A New Approach to Quantifying Landscape Mosaics Developed for the Lao PDR

A key challenge for land change science in general and research on swidden agriculture in particular, is linking land cover information to human–environment interactions over larger spatial areas. In Lao PDR, a country facing rapid and multi-level land change processes, this hinders informed policy- and decision-making. Crucial information on land use types and people involved is still lacking. This article proposes an alternative approach for the description of landscape mosaics. Instead of analyzing local land use combinations, we studied land cover mosaics at a meso-level of spatial scale and interpreted these in terms of human–environmental interactions. These landscape mosaics were then overlaid with population census data. Results showed that swidden agricultural landscapes, involving 17% of the population, dominate 29% of the country, while permanent agricultural landscapes involve 74% of the population in 29% of the territory. Forests still form an important component of these landscape mosaics

Global data set of long-term summertime vertical temperature profiles in 153 lakes

Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change

Global data set of long-term summertime vertical temperature profiles in 153 lakes

Measurement(s) : temperature of water, temperature profile Technology Type(s) : digital curation Factor Type(s) : lake location, temporal interval Sample Characteristic - Environment : lake, reservoir Sample Characteristic - Location : global Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14619009Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change

Send PHARMACOKINETICS AND EXCRETION OF THE 21-AMINOSTEROID ANTIOXIDANT U- 74006F IN RAT AND PERFUSED RAT LIVER

ABSTRACT: U-74006F, 21-(4-(2,6-dipyrrolidinyl-4-pynmldinyl)-1-piperazinyl)-16a

Pyroptosis activates conventional type I dendritic cells to mediate the priming of highly functional anticancer T cells

Background Initiation of antitumor immunity is reliant on the stimulation of dendritic cells (DCs) to present tumor antigens to naïve T cells and generate effector T cells that can kill cancer cells. Induction of immunogenic cell death after certain types of cytotoxic anticancer therapies can stimulate T cell-mediated immunity. However, cytotoxic therapies simultaneously activate multiple types of cellular stress and programmed cell death; hence, it remains unknown what types of cancer cell death confer superior antitumor immunity.Methods Murine cancer cells were engineered to activate apoptotic or pyroptotic cell death after Dox-induced expression of procell death proteins. Cell-free supernatants were collected to measure secreted danger signals, cytokines, and chemokines. Tumors were formed by transplanting engineered tumor cells to specifically activate apoptosis or pyroptosis in established tumors and the magnitude of immune response measured by flow cytometry. Tumor growth was measured using calipers to estimate end point tumor volumes for Kaplan-Meier survival analysis.Results We demonstrated that, unlike apoptosis, pyroptosis induces an immunostimulatory secretome signature. In established tumors pyroptosis preferentially activated CD103+ and XCR1+ type I conventional DCs (cDC1) along with a higher magnitude and functionality of tumor-specific CD8+ T cells and reduced number of regulatory T cells within the tumor. Depletion of cDC1 or CD4+ and CD8+ T cells ablated the antitumor response leaving mice susceptible to a tumor rechallenge.Conclusion Our study highlights that distinct types of cell death yield varying immunotherapeutic effect and selective activation of pyroptosis can be used to potentiate multiple aspects of the anticancer immunity cycle

Modelling feedbacks between human and natural processes in the land system

Abstract. The unprecedented use of Earth's resources by humans, in combination with the increasing natural variability in natural processes over the past century, is affecting evolution of the Earth system. To better understand natural processes and their potential future trajectories requires improved integration with and quantification of human processes. Similarly, to mitigate risk and facilitate socio-economic development requires a better understanding of how the natural system (e.g., climate variability and change, extreme weather events, and processes affecting soil fertility) affects human processes. To capture and formalize our understanding of the interactions and feedback between human and natural systems a variety of modelling approaches are used. While integrated assessment models are widely recognized as supporting this goal and integrating representations of the human and natural system for global applications, an increasing diversity of models and corresponding research have focused on coupling models specializing in specific human (e.g., decision-making) or natural (e.g., erosion) processes at multiple scales. Domain experts develop these specialized models with a greater degree of detail, accuracy, and transparency, with many adopting open-science norms that use new technology for model sharing, coupling, and high performance computing. We highlight examples of four different approaches used to couple representations of the human and natural system, which vary in the processes represented and in the scale of their application. The examples illustrate how groups of researchers have attempted to overcome the lack of suitable frameworks for coupling human and natural systems to answer questions specific to feedbacks between human and natural systems. We draw from these examples broader lessons about system and model coupling and discuss the challenges associated with maintaining consistency across models and representing feedback between human and natural systems in coupled models