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Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8–8·9) vs 4·2 months (3·3–5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49–0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2–5·6] vs 4·2 months [3·6–4·9]; 0·99, 0·77–1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Merrimack Pharmaceuticals.

Increasing biological nitrogen (N) fixation (BNF) in maize production could reduce the environmental impacts of N fertilizer use, but reactive N in the rhizosphere of maize limits the BNF process. Using non-transgenic methods, we developed gene-edited strains of Klebsiella variicola ( Kv 137-2253) and Kosakonia sacchari ( Ks 6-5687) bacteria optimized for root-associated BNF and ammonium excretion in N-rich conditions. The aim of this research was to elucidate the mechanism of action of these strains. We present evidence from in vitro, in planta and field experiments that confirms that our genetic remodeling strategy derepresses BNF activity in N-rich systems and increases ammonium excretion by orders of magnitude above the respective wildtype strains. BNF is demonstrated in controlled environments by the transfer of labeled 15 N 2 gas from the rhizosphere to the chlorophyll of inoculated maize plants. This was corroborated in several 15 N isotope tracer field experiments where inoculation with the formulated, commercial-grade product derived from the gene-edited strains (PIVOT BIO PROVEN® 40) provided on average 21 kg N ha -1 to the plant by the VT-R1 growth stages. Data from small-plot and on-farm trials suggest that this technology can improve crop N status pre-flowering and has potential to mitigate the risk of yield loss associated with a reduction in synthetic N fertilizer inputs.

The iron-sulfur cluster (ISC) is an ancient and essential cofactor of many proteins involved in electron transfer and metabolic reactions. In Arabidopsis, three pathways exist for the maturation of iron-sulfur proteins in the cytosol, plastids, and mitochondria. We functionally characterized the role of mitochondrial glutaredoxin S15 (GRXS15) in biogenesis of ISC containing aconitase through a combination of genetic, physiological, and biochemical approaches. Two Arabidopsis T-DNA insertion mutants were identified as null mutants with early embryonic lethal phenotypes that could be rescued by GRXS15. Furthermore, we showed that recombinant GRXS15 is able to coordinate and transfer an ISC and that this coordination depends on reduced glutathione (GSH). We found the Arabidopsis GRXS15 able to complement growth defects based on disturbed ISC protein assembly of a yeast Delta grx5 mutant. Modeling of GRXS15 onto the crystal structures of related nonplant proteins highlighted amino acid residues that after mutation diminished GSH and subsequently ISC coordination, as well as the ability to rescue the yeast mutant. When used for plant complementation, one of these mutant variants, GRXS15(K83/A), led to severe developmental delay and a pronounced decrease in aconitase activity by approximately 65%. These results indicate that mitochondrial GRXS15 is an essential protein in Arabidopsis, required for full activity of iron-sulfur proteins.

The total demand for and uptake of nutrients by vegetation is rarely quantified or compared across vegetation types. Here, we describe different nutrient use and allocation strategies in neotropical savanna (cerrado) and transitional forest (cerradão) tree communities composed of different species, report leaf nutrient resorption and calculate ecosystem-level nutrient use efficiency. We couple net primary productivity (NPP) estimates with nutrient stoichiometry to quantify nutrient demand and nutrient flows at the whole-stand scale for different components of vegetation biomass. Species from the two vegetation communities showed similar mean nutrient concentrations and nutrient resorption efficiency, except for wood P concentration that was fourfold higher in cerrado than cerradão species. The cerradão showed higher canopy NPP, while fine roots and wood NPP were similar for the two vegetation types. Nutrient requirement in the two vegetation types was dominated by the demands of the canopy, with canopy resorption generally contributing more than 50 % of the total canopy demand for nutrients, while less than 35 % of N, P, K, Ca and Mg were allocated to wood or fine roots. Proportionally, cerrado showed higher nutrient demand from fine roots (over 35 % of the total nutrient demand) and for the wood component (over 13 % of the total nutrient demand), while ∼ 60 %–70 % of the cerradão nutrient demand was allocated to the canopy. The proportional difference in nutrient allocation to the different biomass components suggests cerrado species allocate less nutrients to a given fine root biomass, but more nutrients to a given wood biomass. Our findings suggest that cerradão species are more limited in P and K than cerrado species, inducing higher resorption to compensate for low uptake. Moreover, we found that N uptake for cerradão was higher with lower N use efficiency, i.e. the amount of production per nutrient unit, leading higher N demand compared to the cerrado. This difference in nutrient dynamics explains how similar soils and the same climate dominated by savanna vegetation can also support forest-like formations. Tree species composition is likely the major factor regulating nutrient use, limiting vegetation transitions and influencing nutrient demand at landscape scales.

The present editorial 2020 continues the series of status reports in Environmental Earth Sciences (EES) in previous years 2017 and 2019 (Kolditz et al. in Environ Earth Sci 77: 8, 2018, Kolditz et al. in Environ Earth Sci 79: 11, 2020). The year 2020 coming to an end was heavily influenced by the COVID-19 pandemic affecting all areas of life including research work and, therefore, scientific publishing as well (“Introduction”). One bright spot which shows longevity of journals that produce a quality product is that Environmental Earth Sciences (EES) is celebrating its 45th anniversary of publication. To this extent EES continues the tradition to honor the most cited papers contributing to the 2020 Impact Factor (IF) (“Highly and most cited topics”) and provide information on the current status of EES as well as an outlook to 2021 (“Progress report”)

Drawing on critical theories within and without the international legal discipline, this book offers a fresh approach to the debate on global constitutionalism - an approach that attempts to get beyond the liberal democratic trajectories in which it is currently entrenched.

Truncated tissue factor (tTF)-NGR consists of the extracellular domain of the human TF and the binding motif NGR. tTF-NGR activates blood coagulation within the tumour vasculature following binding to CD13, and is overexpressed in the endothelial cells of tumour vessels, resulting in tumour vessel infarction and subsequent retardation/regression of tumour growth. The aim of the present study was to investigate gadofosveset-based real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in evaluating the initial therapeutic effects of the anti-vascular tTF-NGR approach. DCE-MRI (3.0 T) was performed in human U87-glioblastoma tumour-bearing nude mice. During a dynamic T1w GE-sequence, a gadolinium-based blood pool contrast agent (gadofosveset) was injected via a tail vein catheter. Following the maximum contrast intensity inside the tumour being obtained, tTF-NGR was injected (controls received NaCl) and the contrast behaviour of the tumour was monitored by ROI analysis. The slope difference of signal intensities between controls and the tTF-NGR group was investigated, as well as the differences between the average area under the curve (AUC) of the two groups. The association between intensity, group (control vs. tTF-NGR group) and time was analysed by fitting a linear mixed model. Following the injection of tTF-NGR, the signal intensity inside the tumours exhibited a statistically significantly stronger average slope decrease compared with the signal intensity of the tumours in the NaCl group. Furthermore, the initial average AUC values of mice treated with tTF-NGR were 5.7% lower than the average AUC of the control animals (P<0.05). Gadofosveset-enhanced MRI enables the visualization of the initial tumour response to anti-vascular treatment in real-time. Considering the clinical application of tTF-NGR, this method may provide a simple alternative parameter for monitoring the tumour response to vascular disrupting agents and certain vascular targeting agents in humans.

No detailed description available for \"Toward an Interpretation of the Book of Proverbs\".

The science guiding the EUREC4A campaign and its measurements is presented. EUREC4A comprised roughly 5 weeks of measurements in the downstream winter trades of the North Atlantic – eastward and southeastward of Barbados. Through its ability to characterize processes operating across a wide range of scales, EUREC4A marked a turning point in our ability to observationally study factors influencing clouds in the trades, how they will respond to warming, and their link to other components of the earth system, such as upper-ocean processes or the life cycle of particulate matter. This characterization was made possible by thousands (2500) of sondes distributed to measure circulations on meso- (200 km) and larger (500 km) scales, roughly 400 h of flight time by four heavily instrumented research aircraft; four global-class research vessels; an advanced ground-based cloud observatory; scores of autonomous observing platforms operating in the upper ocean (nearly 10 000 profiles), lower atmosphere (continuous profiling), and along the air–sea interface; a network of water stable isotopologue measurements; targeted tasking of satellite remote sensing; and modeling with a new generation of weather and climate models. In addition to providing an outline of the novel measurements and their composition into a unified and coordinated campaign, the six distinct scientific facets that EUREC4A explored – from North Brazil Current rings to turbulence-induced clustering of cloud droplets and its influence on warm-rain formation – are presented along with an overview of EUREC4A's outreach activities, environmental impact, and guidelines for scientific practice. Track data for all platforms are standardized and accessible at https://doi.org/10.25326/165 (Stevens, 2021), and a film documenting the campaign is provided as a video supplement.

<正>【据Gut 2020年7月报道】题:Alpha-1抗胰蛋白酶对小鼠及人类酒精相关性肝病的影响 (作者Grander C等) 酒精相关肝病 (ALD) 是全球性的医疗问题,治疗方法较为有限。α-1抗胰蛋白酶 (AAT) 在诸多临床前和临床试验中显示出强大的抗炎活性,本研究旨在探索AAT在ALD中发挥的作用。来自奥地利因斯布鲁克医科大学消化内科的Grander等进行了一项包括人类与小鼠实验两部分的研究。在人类研究中,随机选择512例肝硬化患者,对其进行临床特征分析,比较酒精性肝硬化患者与其他肝病病因肝硬化患者的生存率、临床特征及生化指标 (包括血清AAT浓度) 的差异。在酒精性肝硬化患者中,与血清AAT浓度高于120 mg/dl相比,血清AAT浓度低于120 mg/dl的患者发生死亡/肝移植的风险显著增加。多变量Cox回归分析显示,低血清AAT浓度是肝硬化患者独立的生存/移植预测因子。