Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine ...degrading enzyme—arginine deiminase—conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.
A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
www.clinicaltrials.gov (NCT 01287585).
To clone and characterize genes encoding novel cellulases from metagenomes of buffalo rumens. A ruminal metagenomic library was constructed and functionally screened for cellulase activities and 61 ...independent clones expressing cellulase activities were isolated. Subcloning and sequencing of 13 positive clones expressing endoglucanase and MUCase activities identified 14 cellulase genes. Two clones carried two gene clusters that may be involved in the degradation of polysaccharide nutrients. Thirteen recombinant cellulases were partially characterized. They showed diverse optimal pH from 4 to 7. Seven cellulases were most active under acidic conditions with optimal pH of 5·5 or lower. Furthermore, one novel cellulase gene, C67-1, was overexpressed in Escherichia coli, and the purified recombinant enzyme showed optimal activity at pH 4·5 and stability in a broad pH range from pH 3·5 to 10·5. Its enzyme activity was stimulated by dl-dithiothreitol. The cellulases cloned in this work may play important roles in the degradation of celluloses in the variable and low pH environment in buffalo rumen. This study provided evidence for the diversity and function of cellulases in the rumen. The cloned cellulases may at one point of time offer potential industrial applications.
China presently contributes the largest amount of anthropogenic mercury (Hg) emission into the atmosphere in the world. Over the past decade, numerous studies have been conducted to characterize the ...concentration and forms of atmospheric Hg in China, which provide insights into the spatial and temporal distributions of atmospheric Hg through ground-based measurements at widely diverse geographical locations and during cruise and flight campaigns. In this paper, we present a comprehensive review of the state of understanding in atmospheric Hg in China. Gaseous elemental mercury (GEM) and particulate-bound mercury (PBM) measured at the remote sites in China are substantially elevated compared to the background values in the Northern Hemisphere. In Chinese urban areas, the highly elevated GEM, PBM and gaseous oxidized mercury (GOM) were mainly derived from local anthropogenic Hg emissions, whereas regional anthropogenic emissions and long-range transport from domestic source regions are the primary causes of the elevated GEM and PBM concentrations at remote sites. Using 7-9 years of continuous observations at a remote site and an urban site, a slight increase in atmospheric GEM (2.4-2.5 % yr-1) was identified (paired samples test: p < 0.01), which is in agreement with the increasing domestic anthropogenic emissions. Anthropogenic GEM emission quantity in China estimated through the observed GEM / CO concentration ratios ranged from 632 to 1138 t annually over the past decade, 2-3 times larger than published values using emission activity data. Modeling results and filed measurements show dry deposition is the predominant process for removing Hg from the atmosphere, 2.5-9.0 times larger than wet deposition, due to the elevated atmospheric GEM and PBM concentrations that facilitate dry deposition to terrestrial landscapes. Further studies to reconcile the observed and simulated Hg concentrations, to understand the impact of domestic emission reduction on Hg concentration and deposition and to delineate the role of Hg emission and deposition of China in the global Hg biogeochemical cycle, are needed.
Abstract
A quantum thermal machine is an open quantum system coupled to hot and cold thermal baths. Thus, its dynamics can be well understood using the concepts and tools from non-Hermitian quantum ...systems. A hallmark of non-Hermiticity is the existence of exceptional points where the eigenvalues of a non-Hermitian Hamiltonian or a Liouvillian superoperator and their associated eigenvectors coalesce. Here, we report the experimental realization of a single-ion heat engine and demonstrate the effect of Liouvillian exceptional points on the dynamics and the performance of a quantum heat engine. Our experiments have revealed that operating the engine in the exact- and broken-phases, separated by a Liouvillian exceptional point, respectively during the isochoric heating and cooling strokes of an Otto cycle produces more work and output power and achieves higher efficiency than executing the Otto cycle completely in the exact phase where the system has an oscillatory dynamics and higher coherence. This result opens interesting possibilities for the control of quantum heat engines and will be of interest to other research areas that are concerned with the role of coherence and exceptional points in quantum processes and in work extraction by thermal machines.
The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium
, which is assumed to dominate the total extragalactic dispersion. ...Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs
, in at least one case there is evidence for an extreme magneto-ionic local environment
and a compact persistent radio source
. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately Formula: see text parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies
, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
The prognosis of bearings is vital for condition-based maintenance of rotating machinery. This article proposes a systematic prognostic scheme for rolling element bearings. The proposed scheme infers ...the degradation progression by developing a novel health indicator (HI). This novel HI, derived from the spectral correlation, Wasserstein distance, and linear rectification, can reflect the changes in the probability distribution of all cyclic power-spectra over time. In other words, any form of variation in modulation characteristics can be revealed through the proposed novel indicator, even for the weak information buried by the internal or external noise. Furthermore, the developed HI can eliminate random fluctuations that often impair the remaining useful life (RUL) prediction accuracy. Then, a 3 <inline-formula><tex-math notation="LaTeX">{\boldsymbol{\sigma }}</tex-math></inline-formula> criterion-based technique is introduced to divide health stages. After that, the gated recurrent unit network is employed to predict the RUL of the bearing system, integrated with the Bayesian optimization algorithm to tune the optimal hyperparameters adaptively. This renders the establishment of an intelligent prognosis model with high prediction accuracy and generalization ability. Finally, experimental validations are conducted using the run-to-failure datasets of bearings. The obtained results demonstrate that the proposed HI has better monotonicity, and the proposed prognostic scheme can predict the RUL with high accuracy.
The search continues for nickel oxide-based materials with electronic properties similar to cuprate high-temperature superconductors
. The recent discovery of superconductivity in the doped ...infinite-layer nickelate NdNiO
(refs.
) has strengthened these efforts. Here, we use X-ray spectroscopy and density functional theory to show that the electronic structure of LaNiO
and NdNiO
, while similar to the cuprates, includes significant distinctions. Unlike cuprates, the rare-earth spacer layer in the infinite-layer nickelate supports a weakly interacting three-dimensional 5d metallic state, which hybridizes with a quasi-two-dimensional, strongly correlated state with Formula: see text symmetry in the NiO
layers. Thus, the infinite-layer nickelate can be regarded as a sibling of the rare-earth intermetallics
, which are well known for heavy fermion behaviour, where the NiO
correlated layers play an analogous role to the 4f states in rare-earth heavy fermion compounds. This Kondo- or Anderson-lattice-like 'oxide-intermetallic' replaces the Mott insulator as the reference state from which superconductivity emerges upon doping.
Heatwaves are important climatic extremes in atmospheric and oceanic systems that can have devastating and long-term impacts on ecosystems, with subsequent socioeconomic consequences. Recent ...prominent marine heatwaves have attracted considerable scientific and public interest. Despite this, a comprehensive assessment of how these ocean temperature extremes have been changing globally is missing. Using a range of ocean temperature data including global records of daily satellite observations, daily in situ measurements and gridded monthly in situ-based data sets, we identify significant increases in marine heatwaves over the past century. We find that from 1925 to 2016, global average marine heatwave frequency and duration increased by 34% and 17%, respectively, resulting in a 54% increase in annual marine heatwave days globally. Importantly, these trends can largely be explained by increases in mean ocean temperatures, suggesting that we can expect further increases in marine heatwave days under continued global warming.
Marine heatwaves (MHWs) can cause devastating impacts to marine life. Despite the serious consequences of MHWs, our understanding of their drivers is largely based on isolated case studies rather ...than any systematic unifying assessment. Here we provide the first global assessment under a consistent framework by combining a confidence assessment of the historical refereed literature from 1950 to February 2016, together with the analysis of MHWs determined from daily satellite sea surface temperatures from 1982-2016, to identify the important local processes, large-scale climate modes and teleconnections that are associated with MHWs regionally. Clear patterns emerge, including coherent relationships between enhanced or suppressed MHW occurrences with the dominant climate modes across most regions of the globe - an important exception being western boundary current regions where reports of MHW events are few and ocean-climate relationships are complex. These results provide a global baseline for future MHW process and prediction studies.
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