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.
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.
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.
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.
We present a survey for transient and variable sources, on time-scales from 28 s to ∼1 yr, using the Murchison Widefield Array (MWA) at 182 MHz. Down to a detection threshold of 0.285 Jy, no ...transient candidates were identified, making this the most constraining low-frequency survey to date and placing a limit on the surface density of transients of <4.1 × 10−7 deg−2 for the shortest time-scale considered. At these frequencies, emission from Fast Radio Bursts (FRBs) is expected to be detectable in the shortest time-scale images without any corrections for interstellar or intergalactic dispersion. At an FRB limiting flux density of 7980 Jy, we find a rate of <82 FRBs per sky per day for dispersion measures <700 pc cm−3. Assuming a cosmological population of standard candles, our rate limits are consistent with the FRB rates obtained by Thornton et al. if they have a flat spectral slope. Finally, we conduct an initial variability survey of sources in the field with flux densities ≳0.5 Jy and identify no sources with significant variability in their light curves. However, we note that substantial further work is required to fully characterize both the short-term and low-level variability within this field.
Additive layer manufacturing (ALM), using gas tungsten arc welding (GTAW) as heat source, is a promising technology in producing Inconel 625 components due to significant cost savings, high ...deposition rate and convenience of processing. With the purpose of revealing how microstructure and mechanical properties are affected by the location within the manufactured wall component, the present study has been carried out. The manufactured Inconel 625 consists of cellular grains without secondary dendrites in the near-substrate region, columnar dendrites structure oriented upwards in the layer bands, followed by the transition from directional dendrites to equiaxed grain in the top region. With the increase in deposited height, segregation behavior of alloying elements Nb and Mo constantly strengthens with maximal evolution in the top region. The primary dendrite arm spacing has a well coherence with the content of Laves phase. The microhardness and tensile strength show obvious variation in different regions. The microhardness and tensile strength of near-substrate region are superior to that of layer bands and top region. The results are further explained in detail through the weld pool behavior and temperature field measurement.
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